TW378207B - Benzylidene derivatives - Google Patents

Abstract

Benzylidene derivatives having anti-inflammatory activities, which is shown by the following formula I: (I) wherein A is íVCH2- or íVCH2CH2; B is a bond or íVCH2-, -CHOH-, -CO-, -O-, or A and B may taken together form íVCH-CH-; D is >N- or >CH-; R1 and R2 each independently is hydrogen, C1-C5 alkyl or C1-C3 alkoxy; R3 is hydrogen, C1-C5 alkyl, cycloalkyl, C1-C3 alkoxy, arylalkyloxy, heteroarylalkyloxy, C1-C3 alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl, or a group of the formula: -(CH2)n-R4 wherein R4 is hydrogen, hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl, or C1-C3 alkyloxycarbonyl; n is an integer of 0-3.

Description

Revised Date, 88. 8. 25 Supplement Α7 Β7 V. Description of the Invention (24)

MOMO

t-Bu 6 +, n-r341 Ονο: check

71

= \ B 3a

(E-isomer) (Z- 异 «ί 物 I) 8. 3 Printed by Zhengong Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs 1 (Ra = Et) --s- ds- 二 • 隹 =- Ding Qi-4-Wuqian > gg y QI-1. Brillidin-1. 1-dihydrazone (8an? (7) -threate fQa) in diisopropylamine (15.5 * 1 » 110.6 ·· ο1) After 20 minutes, add n-butyllithium to hexane (1.6M »69.5 · 1, 111β · ο1) dropwise in an ice-water bath. After the addition was complete, the mixture was stirred for 15 minutes and the reaction mixture was cooled to -78t: TTP (100 · 1) was then added. »In the reaction mixture, N-ethyl-1,2-iso was added dropwise over a period of 15 minutes. Doxazolyl-1, dioxane 4a (15g, 100.5ββο1), 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6 (25g, 90 · 5lίol) and HMPA (30Bl ) In THF (70β1). The reaction mixture was stirred for another 30 minutes at the same temperature, warmed to room temperature, poured into cold 2N-ΗΠ (100 · 1) and extracted with K ethyl acetate (2 × 250 · 1). Ethyl acetate _ phase is diluted with aqueous hydrogen iodate solution (300 paper sizes are applicable to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) _ _ --- II ------- packing ------ Order ------ line-(Please read the notes on the back before filling out the page) A7 B7

V. Description of the Invention (1) The invention relates to novel benzylidene derivatives with anti-inflammatory activity. Invention of non-steroidal anti-inflammatory drugs such as lysozyme chloride can effectively improve the initial symptoms and acute inflammation of rheumatism, but It is not possible to improve the progressive condition of chronic rheumatism with bone fractures or to treat osteoarthritis, etc. It is also known that it is possible to cause gastric ulcers due to strong effects of urinary substances. Recently, leukotriene αυ has been clearly understood, wait for ltb4, etc. ( It is a metabolite in the metabolic pathway of arachidonic acid and 5-lipoxygenase) is the main mediator of the inflammatory response. It also suggests that interleukin-1 (IL-1) and inflammation in cytokinin In particular, it has a great relationship with chronic rheumatism. Under the aforementioned conditions, compounds that can inhibit the production of both LTB · and IL-1 by Corian are expected to be anti-inflammatory drugs. These compounds are more known to be non-steroidal anti-inflammatory The drug is more useful due to its anticipation that it is effective not only for acute inflammation but also for chronic inflammation such as chronic rheumatism, etc. Many compounds that can be used as anti-inflammatory drugs have been disclosed KOKAI No. 79944/1983, 257967/1986, 42977/1987, 305028/1989, 4729/1990, 256645/1990, 270865/1990, Japanese Patent No. WO 89/503782, etc. To obtain compounds that can effectively treat chronic inflammation and have lower side effects such as gastric disorders, there is a continuing need to develop compounds that can effectively prevent inflammation such as prostaglandin Ea (PGEa), LTB «, IL-1, etc. The inventors have discovered A certain benzylidene derivative can significantly inhibit the production of PGE2 and cytokinins such as LTB4, IL-1, etc., thus completing the present invention. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) --- ---- „-^ --'- 1 installed ------ ordered ------ Quan Yi I (Please read the precautions on the back before filling this page) Staff of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives 3 V. Description of the invention (38 A7 B7 7.2, Bu 7.25 (411, Ling, 2 \ Aroma-11, 2 /? -1-10, 7.42 (111,1 :, < 1 = 2.2 Hz, CH ) I8.50-8.58 (2H, «, Py-H). CaaHaeNaOaS Calculated value: C, 66.63; H, 7.29; N, 6.76; S, 7.73 Test value: C, 66.46; H, 7.18; N, 6.66; S, 7.49. M〇m〇 (t-Bu, / t-Bu

0 S: 'N, 〇 I Y

7

(E / Z mixture) Take off guarantee iii (Ya = take off Bao Jiji) I 11 I n I n Thread (please read the precautions on the back before filling in, page r) Printed by Industrial and Consumer Cooperatives

(E-isomer) 10a

(Z-isocyanate) 10b (R3 = Η) (Υ = C0.C (CH3),) (Κ) -Η- (Di-Di San Ding Mou-4- 筠 V Xiwu Mou. 2-Li 臃ΡΦ 腚 1.1-Diargon servant. 物 now This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) -40-5. Description of the invention (

A7 B7 Task Description Thus, the present invention provides a compound of formula I * ·

Where A is -CHa- or -CHsCHa-; B is a bond or -CHa-, -CHOH-, -CO-, -0, or A and B can be combined to form -CH = CH-; D is > N- _ >CH-; R1 and R »are each independently hydrogen, low iodoalkyl or low sulfoalkoxy; R3 is hydrogen, low alkyl, cycloalkyl, low sulfoalkoxy, arylalkane Aryloxy, heteroarylalkyloxy, low sulfoalkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl, or a group of the formula:-(CHs) n-R4 where R4 is hydrogen Hydroxy, substituted or unsubstituted amine, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl; n is an integer from 0 to 3. Typical compounds of formula I include compounds in which the sulfur-containing heterocyclic ring system of formula I is represented by the following formulae. -------- ΊΙ ^ --.—'— Install ------ Order ------ Huai--(Please read the notes on the back before filling this page) Central Standards of the Ministry of Economic Affairs Printed by Bureau of Consumer Cooperatives D-

Qk yp • S '

D- ⑻ (b) 4 This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Zhan Yue, ::. 'Douyue Yue gt > 88. 8. 25 No 1 A7 B7

CHO 〇, 々〇 + ^ N-Et

OH

V. Description of the invention (52 啻 29 (| ^ -9-7. Even-5- (3.5--diisopropyl--4- 瘅)) ¥ -1.2-Li 噱 睥 if -1. 1- Diargon (87) 4a. P-TsOH ^ ——M ----- pack— (Please read the precautions on the back before filling ^ 4 苋)

Printed by Shellfish Consumer Cooperative of Central Bureau of Quasi-Economics of the Ministry of Online Economics According to a similar method as in Example 1, N-ethyl-1,2-isosiazolidine-1,1-dioxide (4a) (4.9g, 32 8.β? 1) and 3,5-diisopropyl-4-methoxymethoxybenzaldehyde < 6c) (7.51g, 30aaOl) were subjected to an alcohol reaction to obtain 6.07g (50.6%) of an addition compound (7r) White powder. To a solution of the addition compound 7r (5.0 g, 200 mol-) in toluene (100 ul) was added p-toluenesulfonic acid hydrate (200 ng). The mixture is heated to the back. The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) -5 4-A7 B7. 5. Description of the invention (3 ') ° Λ / Ρ D- 〇wP D- I 〇

⑹ (d) 〇wP D-

〇s / 〇: s. / \

D- (e) (f) (Please read the precautions on the back before filling out this page) -In the installation, D is > N- or > CH-. Preferred compounds of formula I include those in which the sulfur-containing heterocyclic ring system in formula I is represented by the following formula.

1T • N- (a-1) q s / 〇: s (N- V3 CH- (a-2) line Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (b-1) qx / 〇 ‘〇

N- (θ-1) qs / p 'O *

N- I 0 (d-1) ϋΐ 5 This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) It is obvious that the formula I can exist in the two (3) stereostructures of the form (E) and (Z). As such, unless otherwise noted, Compound I described in this specification should include (E) and (Z) isomers. For the purposes of the present invention as disclosed and patented, the following terms are defined below. The term "low sulfoalkyl" represents a straight or branched 鲢 C ^ Ce alkyl group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third Butyl, n-pentyl, isopentyl, neopentyl, second pentyl, third pentyl, n-hexyl, neohexyl, isohexyl, second hexyl, third hexyl, heptyl and octyl. Preferably, the low sulfoalkyl group is a straight or branched fluorene ChC * alkyl group, and the most preferred is methyl or ethyl. The term "low alkoxy" represents a straight or branched G-Cb alkoxy group, including methyl, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Second butoxy, third butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, second pentoxy, third pentoxy, n-hexyloxy, neohexyloxy, isohexyloxy Group, a second hexyloxy group and a third hexyloxy group. The preferred low nitrate alkoxy group is G-C3 alkoxy group, and the most preferred is methoxy group. The term "cycloalkyl" stands for C3-C7 cycloalkyl and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C3-Ce cycloalkyl is particularly preferred. The term "aryl" stands for substituted or unsubstituted phenyl or naphthyl. The aryl group may be substituted with one or more substituents selected from a halogen atom, a lower alkoxy group, a lower alkyl group and a nitro group. Examples of aryl include phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,4-diphenylphenyl, 3,4-dimethoxyphenyl, Paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) 6-* I-— ^ ϋ--1- 1 · · · m HI I (Please read the precautions on the back before filling this page), ιτ Line Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^, Description of the invention (5) 4-Dinitrophenyl, phenaphthyl and 2-naphthyl. The term "arylalkoxy" represents a group formed by substituting an aryl group on an alkoxy group as defined above. Examples of arylalkyloxy include benzyloxy, 4-chlorobenzyloxy, 4-methoxybenzyloxy, 3,4-dichlorobenzyloxy, 3,4-dimethoxy Benzyloxy, 4-nitrobenzyloxy, 2-phenylethyloxy, 2- (4-fluorophenyl) ethyloxy, 2- (4-methoxyphenyl) ethyl Ethoxy, p-naphthylmethyloxy and 2-naphthylmethyloxy. The most preferred is benzyloxy. The term "heteroaryl" represents a cyclic radical containing 1-4 heteroatoms. Examples include pyridyl, doxazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxazolyl, triazolyl and tetrazolyl. M pyridyl, thiazolyl * oxazolyl and oxazolyl are preferred for use in the present invention, and Mpyridyl is most preferred. The term "heteroarylalkyloxy" refers to a group formed by substituting a heteroaryl group to an alkoxy group as defined above. Examples include 2-pyridylmethyloxy, 3-pyridylmethyloxy, 4-pyridylmethyloxy, 2-oxazolylmethyloxy, 4-oxazolylmethyloxy, 2 -Doxazolylmethylamino and 4-thiazolylmethyloxy. Examples of "low ore alkylcarbonyl" include ethenyl, propionyl, butyryl, pentamyl, hexyl, heptyl and octyl. Examples of "arylcarbonyl" include benzamyl, 4-aminobenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 3,4-dichlorobenzyl , 3,4-dimethoxybenzyl, 3,4-dinitrobenzyl, benzonaphthyl and 2-naphthylmethyl. The term "substituted or unsubstituted amine methylamine" represents the nitrogen atom selected by the paper size to apply Chinese National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page) . Installation-Line A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (Aminomethylamino, optionally substituted from one or more of the following substituents as needed: lower alkyl, lower nitrane Oxy, hydroxy, fluorenyl, arylalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyloxy and arylalkyloxy. Preferred substituents are oligoalkyl , Sulfoalkoxy and hydroxyl. Examples of substituted aminomethyl groups include N-methylaminomethylmethyl, N, N-dimethylaminomethylmethyl, N-hydroxyaminomethylmethyl, N-methyl -N-hydroxylaminomethyl, N-methoxyaminomethyl, N-methoxy-N-methylaminomethyl, N-ethylaminomethyl ether, Ν, N-diethyl Carbaminyl, N-ethyl-N-hydroxylaminomethyl, N-propylaminomethyl, N, N-dipropylaminomethyl, and N-propyl-N-hydroxylaminomethyl Radical ° pronoun "halogen" Fluorine, chlorine, bromine, and iodine. Examples of "lower alkyloxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl, and tertiary butoxycarbonyl The term "substituted amine group" represents a mono- or di-substituted amine group and the substituents are selected from the lower alkyl and arylalkyl groups as defined above. The compound bb of the present invention is better than E5110 and 8¾ inmethacetin ( indomethacin) (used as a control compound in the following experimental examples) shows excellent in vitro test activity in inhibiting the production of PGE8, LTB4, and IL-1. It was also confirmed in vivo that compound I can inhibit edema and only affect gastric mucosa. It caused a little damage and proved to be an excellent non-steroidal anti-inflammatory agent. The benzylidene derivative of the present invention is novel and can be prepared, for example, by the methods described in (1 > to (4 >) below. However, the present invention is by no means limited to these The compounds prepared by the method include all compounds prepared by any other known method. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 8 —.----;-^-. 1 — --Install ------ order ------ line - - 1 (Please read the notes on the back of this page and then fill in) A7 B7 V. invention is described in ((1) 0Rb R1, Shang ^ R2

CHO 6 B-d ° 〇 R3 4

acid

9 (Please read the precautions on the back before filling out this page). Assemble. Order A, B, D, R1, Ra, and! 13 in the printed format of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs as above, and Re is Hydrogen or hydroxyl protecting group. One of the starting compounds, the sulfur-containing compound 1 can be prepared according to the following reaction formula, for example. r3nh2 2 q ⑻ cr ^ 'S02CI —CI ^^^ SOpNHR3 base ㈧ r3nh, 0 S; -N 〇 R3 4' 2 base R3 is as defined above. 9 This paper size applies to Chinese National Standards (CNS) Λ4 specifications (210X297 mm) A7 B7 V. Statement of invention printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (8) 3-chloropropylsulfonyl chloride L1 and amine 2 _ Reaction to obtain sulfamidamide intermediate 3_1. The reaction is carried out in the presence of age (A). If necessary, it can be carried out in a solvent. The solvent is poured from ether, chloroform, methylene chloride, methylene chloride * dichloroethane, tetrahydrofuran, and dimethoxyethyl. Alkane, diethoxyethane, benzene, toluene, xylene, ethyl acetate, methyl acetate, etc. The solvent may contain water. The amine (R3NHa) may be a hydrochloride salt. If necessary, the age of use (A) contains aging alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium sulfonate, potassium carbonate, sodium bisulfate and Potassium hydrogen acetate, etc .; and organic ages such as pyridine, 4-N, N-dimethylamino eftidine (DMAP), triethylamine, diisobutylethylamine, 1,8-diazinebicycle [ 5,4,0] Undecylen-7-ene 〇81]), 1,4-diazinebicyclo [2,2,2] octane (0 6 8 (: 0), etc. When using alkali gold fluorene During the test, if necessary, it is better to add a phase transfer catalyst. Examples of preferred phase transfer catalysts are fourth ammonium salts such as N-benzyltrimethylammonium salt * tetrabutylammonium salt, etc. The reaction with the fluorene-containing compound il can be performed in the presence of the test (B) in a solvent selected from the foregoing. An anhydrous solvent such as dimethylamine, dimethylformamide, etc. is preferred. In addition to the foregoing, Sodium hydride and lithium hydride can be used as the base (B). In addition, the fluorene-containing compound can be prepared from compound L1 at one time without isolation of the sulfonamide intermediate 3-L. In this case, the reaction between compound L1 and amine 1 is in a suitable solvent Within 2 equivalents Solvents and solvents can be selected from the above examples, but the most preferred ones use sodium hydride as the age and dimethyl methylamine as the solvent. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)- -1 ------- LI installation ------ order ------ 涞--(Please read the notes on the back before filling out this page) 10 V. Description of the invention (A7 B7 s; 1) R3NH2 '〇' ° 2) POCI3-νΛ〇R3 5: 4: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs In addition, the expected sulfur compounds can also be obtained from commercially available 7-5l! (See the reference example). In other words, the compound 5_L is reacted with an amine (R3NH,> and treated with a dehydrating agent. The reaction can be performed without a solvent, but if necessary, it can be performed under the aforementioned solvent. Useful dehydration Examples include those commonly used, such as phosphonium chloride, sulfonium chloride, phosphorus pentachloride, phosphorus pentoxide, etc. M phosphorus gas is preferred. Re in the compound represents hydrogen or a hydroxyl protecting group. The hydroxyl protecting group contains methoxy Methyl, methoxyethoxymethyl, trimethylsilyl and tert-butyldimethylsilyl. Preferred RB is a hydroxyl protecting group , Especially methoxymethyl. The aldol reaction between the compound obtained above and i is performed in a suitable solvent in the presence of < C). Examples of oysters (C) include organic lithium salts, such as n-butyllithium, Second butyllithium, third butyllithium, phenyllithium, lithium diisopropylamidamine, lithium diethylamidamine, lithium hexamethyldisilazane, etc .; and gold tests such as sodium hydride and third Lithium butoxide, etc. Especially preferred is lithium diisopropylamidide or lithium hexamethyldisilazane. Examples of the reaction solvent include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and diethoxyethane Etc .; or hydrocarbon solvents such as n-hexane, cyclohexane and the like. If necessary, the reaction is preferably performed in the presence of a chemical agent as a lithium metal complex, such as tetramethylethylenediamine, hexamethylphosphoniumamine and the like. This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 11 (Please read the precautions on the back before filling out this page)-Pack-Five Invention Instructions (ίο 蓄; '' Α7 Β7 The reaction is based on- The temperature range is from 80 ° C to + 50TC, and the lower temperature range is preferred. Aldol addition compound: L is converted into a mixture of compounds 8_ and 0_ in the presence of an acid. Examples of acids include organic acids such as trifluoroacetic acid, P-toluenesulfonic acid, clavulanic acid, etc .; and inorganic acids such as sulfuric acid, hydrochloric acid, etc. Ordinary dehydrating agents such as sulfenyl chloride, methanesulfonyl chloride, aluminum chloride, phosphine gas, pentachloride can be used. Phosphorus, etc. The preferred reaction is performed by heating in the following solvents: aromatic hydrocarbons such as benzene, toluene, xylene, etc .; halogenated halides such as chloroform, methylene chloride, dichloroethane, etc .; or ether solvents such as tetrahydrofuran, dimethyl Oxyacetam, diethoxyethane, etc.

(E / Z mixture) 8 1 (Please read the precautions on the back before filling this page)

'II Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Appropriate rule paper for quasi-standard countries

Ns centimeter A7 B7 V. Description of the invention (1 The test in the above formula (C > is as defined above. Υ represents an N protecting group such as a third butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, a 4-methoxybenzyl group, 3 , 4-dimethoxybenzyl, 4-nitrobenzyl, etc. The reaction conditions for aldol reaction are similar to those described in the above reaction Figure 1. Conversion of aldol addition compound L to a mixture of compounds i0a and m The dehydrating agent and deprotecting agent used in the reaction include p-toluenesulfonic acid and trifluoroacetic acid, aluminum gasification, titanium tetrachloride, etc. The conditions such as the reaction solvent, temperature and the like are similar to those described in the reaction figure 1. (E) Deprotection of the mixture of-and (Z) -isomers gives the compound iiM m of formula I (where D is > N- and R3 is H). (3)

(Please read the notes on the back before filling this page).

10 r3-x m (D) Alkylation Methylation Carboxylation Alkoxycarbonylation

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The desired substituent R3 in this reaction is added to the compound of the present invention such as Formula I (where D is > ^ and R3 is H) to obtain each pyrene derivative. When R3-X is an alkylating agent, the rhenium (D) used includes rhenium metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bisulfate, potassium bicarbonate, lithium hydroxide, etc .; or organic Tests such as Pftidine, triethylamine, diisopropylethylamine and so on. The alkylation reaction is preferably carried out using sodium hydroxide or potassium carbonate in the presence of a suitable fourth ammonium salt as a phase transfer catalyst. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 13 '~~~ V. Description of the invention (A7 B7 If R3X is a brewing agent, it is better to use organic age (such as pyridine, 4-dimethyl Aminopyridine, triethylamine, diisopropylethylamine, etc.) are used as the age (0). When R3X is a carbamidine or an alkoxycarbonylating agent, an organic lithium base (such as n-butyllithium) is preferably used. , Lithium hexamethyldisilazane, lithium diisopropylamidamine) as test (D). The present invention is not limited to these tests. Organic bases such as pyridine, triethylamine, diisopropylethyl can also be used. Amines, etc. or pre-tested chrysophylline (4)

8J off protection

11a 11b (Please read the precautions on the back before filling out this page)-Install i Printed compound I of formula I 112_ and 11] 2_ (where D is> N- and R3 is OH) It is obtained through debenzyl compounds 8_ and 1 using a deprotecting agent. Deprotection is carried out by hydrogenation in the presence of a rake / steel or platinum oxide, or using a Lewis acid such as lithium gasification, titanium tetrachloride, etc., if necessary, together with anisole, 2,6-di- Third butylphenol and the like are carried out. In addition to halogenated hydrocarbons such as dichloromethane, gas-form, dichloroethane, etc., nitromethane, benzene, toluene, xylene, etc. can be used as a reaction solvent. This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 14 V. Description of the invention (l3

A7 B7 The methods listed in (1), (2), (3), and (4> above can be roughly applied to the production of the compound of formula I in the present invention, and are specifically illustrated in the following Examples 1-35 ° The compound I of the present invention is also It can be generated by treating a novel compound of the following formula by using ethyl geranate equal to a conventional dehydrating agent such as triethylamine:

And split the ring to obtain the compound of the following formula (please read the precautions on the back before filling this page) -pack.

Examples of dehydrating agents printed by the Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs include ethyl chloroformate, triethylamine, phosphonium chloride, sulfenyl chloride, DCC (dicyclohexyl formamidine sublime) and the like. This method is roughly applicable to the preparation of the compound of formula I of the present invention by selecting an appropriate starting compound and reaction conditions. The compound I of the present invention can be administered orally or parenterally as an anti-inflammatory agent. As an example, M is administered orally. The compounds of the present invention can be formulated into solid formulations such as lozenges, powders, granules, capsules, etc .; solutions; oil suspensions; liquid formulations such as syrups, elixirs, etc. . For example, the parenteral administration of MU can be formulated into water or oily injection suspensions or for external use. The paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) 15 lines --- I. Ministry of Economic Affairs Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards 5. Description of the invention (14 · ϋ Preparations. In the preparation of formulations, conventional excipients, binders, lubricants, water solvents, oil solvents, emulsifiers, suspensions, etc. can be used. Other additives such as preservatives, stabilizers, etc. may also be included. Although the appropriate daily doses of the compounds of the present invention will vary depending on the route of administration, the age, weight and condition of the patient, and the type of disease being treated, taking adult patients as an example, Oral administration is roughly between 10-500 ag, preferably 50-100 mg, while enteral administration is slightly between 250 mg, preferably 5-10 mg, divided equally into 1 to 5 administrations. The following examples are provided to further The present invention is exemplified without limiting its scope in any way. The abbreviations used in the examples are defined as follows: LDA = lithium diisopropyl amine; MOM = methoxymethyl; P_TsOH = p-toluenesulfonic acid; THF = tetrahydrofuran ; DMF = Ν, -Dimethyl methylamine; HMPA = hexamethylphosphamide; 1 ^ heart 05 = lithium hexamethyl disilazane; 081) = 1,8-diazodicyclo [5,4,0] ten Monosulfo-7-ene; and DIBAL = diisobutylaluminum hydride.

For 3-chloropropyl sulfonic acid fermentation gas 1 (6.1g, 34_5mmol) Yuyue (25ml This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 16 -------- LI Pack ----- ^ Order I ------ line i (Please read the notes on the back before filling this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (15) In the solution, ethylamine (70% aqueous solution, 4.4 g, 68.3 mmol) was added dropwise over 15 minutes with stirring under ice cooling. The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo. Benzene (100al ) Added to the residue and removed the solvent by vacuum distillation. Ether (150B1) was added to the residue and the insoluble materials were removed by filtration. The ether was removed by vacuum distillation of the filtrate to obtain 6.96 g (yield 100%) of crude N-ethyl. 3-Methyl-3-chloropropylsulfonamide (intermediate 3a) is colorless crystals (η · ρ · = 30-32υ). The intermediate 3a (6.96g, 34.5 1111〇1) is at 1'1 ^ (5 〇1 «1) was slowly added sodium hydride (60% in oil, 1.52g, 38.0mmol) over 15 minutes with stirring under ice cooling. The reaction mixture was stirred at room temperature for another 30 minutes. Ether (50ml) was added. )Rear The mixture was filtered to remove insoluble materials and the filtrate was vacuum distilled to remove the solvent to obtain 4.93g (96%) of the mesh compound ^ as a pale yellow oil. IR (CHCl3) cm-1: 3018,2976,2868,1452,1306 , 1220,1179, 1129,1015. NMR (CDC13) S: 1.24 (3H, t, J = 7.4Hz, CH3), 2.28-2.42 (2H, m, CHs), 3.10 (2H, q, J = 7.4Hz , CHa), 3.15 (2H, t, J = 7.6Hz, CHa), 3.22-3.29 (2H, m, CHa). Preparation Example 2 (R3 = Me) N-Shenmou-1. 2-Li Post Pyridine-1. 1 -diammonium compound Uh) 3-Gaspropylsulfonyl chloride 1 (6.8g, 94.9mmol), methylamine HC1 (13.5g, 200mmol) and potassium succinate (27.6g, 200mmol) were added in order Ethyl acetate (500ml). After adding vaporized N-benzyltrimethylammonium (about 200 »g), the resulting mixture was stirred at room temperature for 2 hours and dehydrated over anhydrous sodium sulfate. The mixture is filtered through a small amount of silica gel and the filtrate is concentrated in a vacuum. The paper size is applicable to the Chinese National Standard (CNS) 8-4 specifications (210X 297 mm) _ _ (Please read the precautions on the back before filling this page). A7 B7

V. Description of the invention (16 to give 12 g (74%) of crude N-methyl-3-chloropropylsulfonamide (intermediate 3b) as a pale yellow oil. In intermediate 3b (11.79g, 68.69mmol) in benzene (300 ml) was added to DBU (10.79 ml, 72.12 mmol), and the resulting mixture was stirred at room temperature for 24 hours and filtered through a small amount of silica gel. The filtrate was thinned when the preserved food was removed in vacuo (7_0 g was obtained) (75%) mesh hazel compound 4b colorless solid (m_ρ · = 36-40t). IR (CHCl3) cm-1: 3016,1451,1307,1218,1187,1127. NMR (CDC13) S: 2.27-2.42 ( 2H, m, CHa), 2.69 (3H, s, CH3), 3.U-3.20 (2H, m, CHa >, 3.22 (2H, t, J = 6.8Hz, CHa). Preparation Example 3 (R3 = CHaCH (CH3) a) N-ridine even-1.2-rixazole Qg-〗.〗-Two. Serum (4d 3-chloropropylsulfonium 1 (7.08g, 40mraol), isobutylamine (7.3g, 100mmol) and sodium hydrogen mineral acid (3.36g, 40mmol) were sequentially added to a mixture of ethyl acetate (200ml) and water (20ml). To this mixture was added N-benzyltrimethylammonium chloride ( About 100 mg). The resulting mixture was stirred at room temperature for 3 hours, and then treated in a manner similar to that described in Preparation Example 2 to obtain 8.19 g (96%) of crude N-iso 3-Gaspropylsulfonamide (intermediate 3c) showed colorless crystals (mp = 68-6910). To a solution of intermediate 3c (4.27g, 20mmol) in benzene (60ml) was added DBU (3.3ml, 22®mol) and the reaction mixture were treated in a manner similar to that described in Preparation Example 2 to obtain 3.37 g (95%) of the head compound 4c as a colorless oil. IR (CHCl3) cm-1: 3016, 2956, 1465, 1304 , 1226,1131,1024. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) ------------ LI installed -------- Order ---- --Line (Please read the notes on the back before filling out this page) Printed by the Consumers 'Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 18 B7 B7 V. Printed Invention Notes by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (17_ NMR (CDC13) §: 0.95 (6H, d, J = 6.6Hz, (CH3) *), 1.75-1.96 (1H, m, CH), 2.27-2.42 (2H, m, CHa), 2.80 (2H, d, J = 7.4Hz > (Please read the precautions on the back before filling this page) CH2), 3. 10-3. 19 (2H, iB, CHa), 3.24 (2H (t, J = 6.8Hz, CHa). Mian Preparation Example 4 (R3 = cyclopropyl) N-Clui-U-Li Yingying ng-1.1-digas (4d) 3-chloropropylsulfonyl chloride 1 (7.08g, 40mmol), propylpropylamine ( 6.0g, 105aB0l) Acid hydrogen sodium (3.7g, 44mmol) was added ether (200ml > the mixture with water (LoAL) of. The resulting mixture was treated in a manner similar to that described in Preparation Example 3 to obtain 8.0 g (about 100%) of crude N-cyclopropyl-3-chloropropylsulfonamide (intermediate 3d) as a crystal (101. = 48-49.51¾). The intermediate 3d (l-98g, 10amol) was reacted with DBU (1.65ml, 11 mnol) in benzene (30 · 1). When reacted in a manner similar to that described in Preparation Example 2, the reaction mixture obtained 1.40g (87% ) Compound 4d was a pale yellow oil. IR (CHC13) cm-1: 3016,1309,1221,1140,1026. NMR (CDC13) S: 0.60-0.85 (4Η, ι », cyclopropyl >, 2.20-2 · 40 (3Η, m , CH »+ CH), 3.15-3.25 (2H, m, CHa), 3.32 (2H, t, J = 6.6Hz, CHa). Le Bei Li R (R3 = -CHaCH.CHa) N-TF Halide (4e) 3-chloropropylsulfuric acid 1 (7.08g, 40iiiB0l), n-propylamine (5.90g, 100nmol), potassium sulfonate (5-52g, 40mmol) and a small amount of N-benzyl chloride Methyl ammonium (about 100 mg) was stirred in a mixture of _ (200ml) and water (20 · 1) for 3 hours. The reaction mixture M was similar to that described in Preparation Example 2 19 This paper is in accordance with the Chinese National Standard (CNS) A4 specification ( 210X297 mm) A7 B7 V. Description of the invention 8. 8.Og (about 100%) crude N-n-propyl-3-chloropropylsulfonamide (middle) Compound 3e) is crystalline (^^ = 47.5-4810). The intermediate 3e (2.0 g, 10 mmol) is reacted with DBU (1.65 ml, 11 mmol) in benzene (30 ml) in a similar manner as described in Preparation 2 and 1.41 g (86%) of compound 4e was obtained as a pale yellow to colorless oil. IR (CHCl3) ca-1: 3018,2962,2868,1304,1224,1130,1019. NMR (C DC19) 5: 0.96 (3H, t, J = 7Hz, CH3), 1.52-1.72 (2H, a, CH «), 2.28-2.42 (2H, m, CHa), 2.94-3.04 (2H, b, CH, ), 3.10-3.20 (2H, b.CH8), 3.25 (2H, t, J = 6.7Hz, CHe). Shearing example 6 (R3 = 0CH,) N- 田 氤 某 -1.2-piperidine- 1.1.1-Diargon hydride UH 3-Gaspropylsulfonyl chloride 1 (7.08g, 4BBl), 0-methylhydroxylamine HC1 (3.76g, 40mmol) and potassium carbonate (5-80g, 42mmol) Μ Reaction in a manner similar to that described in Preparation Example 5 gave 7.02 g (94%) of crude N-methoxy-3-chloropropylsulfonamide (intermediate 3f) as a colorless to pale yellow oil. Intermediate 3f (6.25 g, 33-3 mmol) and sodium hydride (60% in oil, 1.47s, 36.7 mmol) were reacted in a manner similar to that described in Preparation Example 1 to obtain 3.70 g (73%) of the eye-dwelling compound 4f as a colorless oil. IR (CHCl3) cm-1: 3022,1355,1249,1222,1165,1138,1035,1011. NMR (CDC13) 5: 2.37-2.50 (2H, m, CHe), 3.20-3. 14 (2H, m , CHa), 3.50 (2H, t, J = 7.0Hz, CHa), 3.81 (3Ht s, 0CHa). Preparation example 7 (R3 = 0CH * C6Hb) 4g) (Please read the notes on the back before filling this page)

、 1T This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 20

A 7 i 'Explanation of the invention (igfSIl 3-Gaspropylsulfonium gas 1 (30.28g, 0.17mmol), 0-benzylhydroxylamine HC1 (27.3g, 0.17β · ο1), potassium sulfonate (50g, 0.36m) »Βο1) and tetrabutylammonium sulfide (about 500» g) were reacted with each other in a mixture of ft and water (1: 1) (100ml) at room temperature for 24 hours and the reaction mixture was extracted with ethyl acetate. The extract was extracted in silica Column chromatography was performed on the gel. Ethyl acetate / n-hexane (1: 4) mixture was used to dissolve the obtained fraction. 18.4 g (41%) of crude N-benzyloxy-3-aminopropylsulfonyl chloride was obtained. (Intermediate 3g) was a pale yellow oil. To a solution of the intermediate 3g (18.4g, 69.9mmol) in THF (150ml) as above was added sodium hydride (60% in oil, 2.94g, 73.4nnnol), and similar preparation The reaction was carried out in the manner described in Example 1. The product was subjected to column chromatography on a silica gel. 10.75 g (68%) mesh was obtained from the fractions obtained using a mixture of ethyl acetate / n-hexane (1: 5). 4g of hazel compound is colorless crystal. M.p. = 52-54¾ IR (CHCl3) cm-1: 3022, 2956, 1453, 1354, 1165, 1140, 1081, 1000. NMR (CDC13) 5: 2.30-2.48 (2H , m, CH2), 3.04-3.14 (2H, ni, CH8), 3.45 (2H, t, J = 6.9 Hz, CHa), 5.00 (2H > s, 0CH8), 7.30-7.45 (5H, ip, C6H,). Preparation example 8 (R3 = 4-methoxybenzyl) argon benzyl)-1.2- Lipyridine-1. 1 -Diargon servant (4h) 3-Gaspropylsulfonyl chloride 1 (17_7g, 0.1mmol), p-methoxybenzylamine (15.0g, 0.11minol) and sodium bicarbonate (8_4g, 0.1i0in〇U in a mixture of ethyl acetate (400ml) and water (40ml) at a similar paper size to the Chinese National Standard (CNS) A4 specification (210X297 mm) -2 1 _- -------: ---- L — install ------ order ------ line; one (please read the notes on the back before filling this page) Ministry of Economic Affairs Zhongli Standard Bureau Printed by the Employee Consumption Cooperative V. Description of the invention (20 Μ A7 B7 Printed by the Employees' Cooperative Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Printed by I. The method described in Example 3 was used to obtain 19.1g (69%) of crude N- (4 -Methoxybenzyl) -3-propanylsulfonamide (intermediate 3h) showed colorless crystals (mp = 78-80 * 0). The intermediate was reacted for 3 h (ll.llg, 40bbo1) with DBU (6.6 · 1,40 »· 〇1) in benzene (150ml). The resulting mixture was treated in a manner similar to that described in Preparation Example 2 to obtain 8.89 g (92%) of the mesh hydrazone compound as crystals in 4h (B · P. = 48-51%). IR (CHC13) ci · -1: 3016.1612, 1511, 1304, 1245.1136, 1034, NMR (CDCU) 5: 2.20-2.38 (2H.a, CHe), 3.09 (2H, t, J = 6.8Hz, CHa), 3.14-3.24 (2H, m, CHa), 3.81 (3H, s, 0CH3), 4.12 (2H, s, CHa), 6.84-6.94 (2H, iB, CHa), 7.22-7.32 (4H, in, 4x Aromatic-H >. Preparation Example 9 (R3 = 3,4-dimethoxybenzyl) (3.4-dimethylformamide ¥ even) -1.2-Preferred_pyridine-1.1-diargonide (4;) 3-chloropropylsulfonyl chloride 1 (8.85g, 50m «ol), 3,4-dimethoxybenzylamine (9.0ml, 60mmol) and potassium carbonate (4.13g, 30mmol) were similar to those described in Preparation Example 2 The reaction was carried out to obtain 14.5g (94%) of crude N- (3,4-dimethoxybenzyl) -3-aminopropylsulfonamide (intermediate 3). The intermediate 3i was similar to the preparation example. Obtained compound 4i (yield: 69%) when treated in the first method. IR (CHC13) cm-1: 3018, 1516, 1307, 1262, 1225, 1155, 1138, 1027. NMR (CDC1S) 5: 2.22-2.38 (2H, m, CH〇, 3. 11 (2H, t, J = 6.7 Hz. CH »), 3.16-3.25 (2H, m, CHa), 3.88 (3H, s, 0CH3), 3.89 (this Paper size applies to China National Standards (CNS) 8 4 specifications (210 × 297 mm) 22 (Please read the precautions on the back before filling out this page)-Packing,? Τ A7 B7 5 Description of the invention (21 3H, s, CH3>, 4. 12 (2H, s, CHa), 6.79-6 · 91 < 3Η, κ, 3 × aromatic-H) Preparation Example 10 (R3 = CgH.) H -Jumou-1.2-Lipipyridine-1.1-Dihelium. Ui) 3-Gasylsulfonyl chloride 1 (1.456g, 8.23BB0l) M Cools to -20 with M for about 5 minutes To -3010, a solution of aniline (0.5 · 1, 8 · 23ϋ · 01) in pyridine (5 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo and the residue was Column chromatography was performed on a silica gel. Using a mixture of ethyl acetate / n-hexane (1: 2), 1.683 g (88%) of N-phenyl-3-chloropropylsulfonamide ( Intermediate 3g) was a yellow oil, and M was obtained in a similar manner to that described in Preparation Example 1 to obtain compound 4j as a pale yellow solid (yield 57 96). IR (CHC13) cm-1: 3020,1598,1495,1315,1139. NMR (CDCU) 5: 2.46-2.60 (2H, m, CHa), 3.34 (3.42 (2H, m, CHa), 3.78 (2H, t, J = 6.6Hz, CH8), 7.10-7.40 (5H, m, CeHe). Preparation Example 11 (R3 = 4-Gaphenyl) N-f 4-Garong)-1.2-based spleen Pyridine-1. 1 -diargonide (4k) According to a similar method described in Preparation Example 10, 3-chloropropylsulfonyl chloride was reacted with 4-aeroaniline in pyridine to obtain N- (4-aerophenyl). -3-Gaspropylsulfonamide (intermediate 3k) (yield 93%). Intermediate 3kM was treated in a similar manner to that described in Preparation Example 2 using DBU to obtain the compound 4k (68% yield) as colorless crystals. (M_P. = 110. 5-111. 5C). IRiKBrJcm-1: 3010, 2960, 1595, 1493, 1300, 1267, 1131. NMR (CDC13) 5: 2.47-2.61 (2H, m, CHa) (3.35- 3.43 (2H, m, --------- Ί ---. LI installation ----- I order ----- quan (Please read the precautions on the back before filling this page) Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China Standards for this paper are applicable to Chinese National Standards (CNS) A4 (210 X 297 mm) -23-23 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 22) CHS), 3.76 < 2H, t, J = 6 .4 Hz, CH >, 7. 16-7.36 (4H, m, 4x aromatic-fluorene). Clipping Example 1 2 (R3 = 2-Bttpyridyl) M- f 2-nH ·· pyridyl) -1.2- In a similar manner, pyridine-1. 1-diglyphin is unreacted. According to a similar method as described in Preparation Example 10, 3-chloropropylsulfonic acid is reacted with 2-aminopyridine to obtain N- (2-Btfc pyridyl) _3. _Chloropropylsulfonamide (Intermediate 31) is a pale yellow solid (yield 54%). The intermediate 31 (2.138 g, 9.11 mmol) was added to a solution of DMF (30 ml) under ice-cooling. Sodium chloride (60% in oil, 401 mg, 10 mmol). The resulting mixture was stirred at 851 for 30 minutes and the solvent was removed by vacuum evaporation. The residue was subjected to column chromatography on a silica gel. Ethyl acetate / hexane was used. In a fraction obtained by dissolving a mixture of alkanes (1: 1), 1.806 g (100%) of mesh 檷 compound 41 was obtained as a yellow solid. IR (CHC13) cid-1: 3022,1592,1473,1434,1 139. NMR ( CDC13) 5: 2.47-2.60 (2H, m, CHa), 3.43 (2H, t, J = 7.5 Hz, CHa), 4.05 (2H, tJ = 6.6Hz, CHa), 6.88-7.02 (lH, m, CH ), 7.26-7.35 (lH, m, CH), 7.58-7.70 (lH, iH, CH), 8.33 (lH, d > J = 4.4Hz, CH). JLMll (R3 = 3-pyridyl) N- (Pyrimidine)-1.2-2 knee knees-1. 1-two shame (4m) In a similar manner as described in Preparation 10, 3-chloropropylsulfonyl chloride (17.28 g, 41.1 mmol) and 3-limylpyridine (4.6 g, 49.3 mmol) were reacted in pyridine (15 ml) to 4.50g (46%) coarse N- (3-Bitpyridine basic paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 0X297mm) IJ ---- 1 --- 丨 installation ---- --Order ------ Quan (Please read the precautions on the back before filling this page) 24 A7 B7 V. Economic and Deng Central Standards Bureau Staff Consumer Cooperatives Printed Invention Description (23)) 3-chloropropane Sulfamethoxamine (intermediate 3ra) was a colorless solid. Intermediate 3m (232mg, 0.988mmol) Μ treated in the same manner as described in Preparation Example 12 using sodium hydride (60% in oil, 43-5mg, 1.09mmol) in DMF (5ml> to give 190mg (97%) mesh compound 4m Colorless solid IR (CHC13) cib-1: 3022,2960,1590,1484,1428,1319,1142. NMR (CDCla) 5: 2.53-2.67 (2H, m, CHa), 3.38-3.45 (2H, m, CHa), 3.83 (2H, t, J = 6.6Hz, CHa), 7.28-7.36 (1H, m, CH), 7.73 -7.79 (1H, m, CH), 8.41 (1H, d, J = 4.6Hz, CH), 8.46 (lH, d, J = 2.4Hz, CH). Preparation example 1 4 (R3 = 4-pyridyl) N- (4-PH: pyrimidine)-1.2-Li favor _ pyridine- 1.1-Diarginine (4n) in 3-chloropropylsulfonyl chloride (3ml, 24.7mmol) and 4-aminopyridine (2.32g, 24.7mo1) in DMF (25ml) in K5 minutes Sodium hydride (60% in oil, 2.17g, 54.3min) was added slowly with stirring under ice cooling. After stirring for another 30 minutes at 501, the reaction mixture was subjected to column chromatography on silica gel. From the eluate obtained using a mixture of dichloromethane / methanol (10: 1), l-294g (27%) of the mesh compound 4η was obtained as a yellow solid. IRiCHCUJcm-1: 3024, 2956, 1597, 1504, 1320, 1143. NMR ( CDC 13) 5: 2.53-2.67 (2H, m, CHa), 3.43 (2H &t; t, J = 7.6 Hz, CHa), 3.81 (2H, t, J = 6.6Hz, CH.), 7.08 (2H, d, J = 5.4Hz, CH), 8.49 (2H, d, J = 5.4Hz, CH). This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) I ------;- --LI Pack ------ Order ------ Quan (Please read the notes on the back before filling in this page) 25 Month, Month, 88. 8. 25 Supplement Α7 Β7 V. Invention Instructions (24)

MOMO

t-Bu 6 +, n-r341 Ονο: check

71

= \ B 3a

(E-isomer) (Z- 异 «ί 物 I) 8. 3 Printed by Zhengong Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs 1 (Ra = Et) --s- ds- 二 • 隹 =- Ding Qi-4-Wuqian > gg y QI-1. Brillidin-1. 1-dihydrazone (8an? (7) -threate fQa) in diisopropylamine (15.5 * 1 » 110.6 ·· ο1) After 20 minutes, add n-butyllithium to hexane (1.6M »69.5 · 1, 111β · ο1) dropwise in an ice-water bath. After the addition was complete, the mixture was stirred for 15 minutes and the reaction mixture was cooled to -78t: TTP (100 · 1) was then added. »In the reaction mixture, N-ethyl-1,2-iso was added dropwise over a period of 15 minutes. Doxazolyl-1, dioxane 4a (15g, 100.5ββο1), 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6 (25g, 90 · 5lίol) and HMPA (30Bl ) In THF (70β1). The reaction mixture was stirred for another 30 minutes at the same temperature, warmed to room temperature, poured into cold 2N-ΗΠ (100 · 1) and extracted with K ethyl acetate (2 × 250 · 1). Ethyl acetate _ phase is diluted with aqueous hydrogen iodate solution (300 paper sizes are applicable to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) _ _ --- II ------- packing ------ Order ------ line-(Please read the notes on the back before filling in the page) 5 'Invention description (25 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed by ml) and saturated saline (300ml) washed, Μ anhydrous sodium sulfate was dried and evaporated under vacuum to remove the solvent. The residue was purified by column chromatography on silica gel using n-hexane / ethyl acetate (4: 1 to 1: 1) to obtain 21.3g (55% ) Aldol addition compound 7a is a colorless solid. To a solution of addition compound 7a (8.5 g, 19.9 μ1) in toluene (150 ml) was added p-toluenesulfonic acid hydrate (2.49 g, 13 inmol). The resulting mixture was heated The mixture was refluxed for 30 minutes, then poured into a dilute aqueous solution of sodium hydrogen sulfonate (150 · 1) and extracted with ethyl acetate (150 ml x 2). The organic layer was washed with water (150 »1) and saturated brine (150al), and dried without water. The solvent was removed by sodium sulfate drying and vacuum evaporation. The residue was subjected to column chromatography on silica gel. By using n-hexane / ethyl acetate (3: 1) In the dissociation fraction, the compound 9a (376mg, 70%) and 8a (2.59g, 36%) were sequentially obtained. Compound 8a: mp = 135-1371. IRiKBrJcm-1: 3610, 3440, 2970 , 2880,1645,1597,1430, 1290,1173,1151,1139. NMR (CDC13) S: 1.29 (3H, t, J = 7.2Hz, CH3), 1.45 (18H, s, 2 XBut), 3.07-B .19 (4H > m, CH2) > 3.28 (2H, q (J = 7.2Hz > CHil), 5.50 (1H, s, OH), 7.24-7 · 26 (3H, m, 2X aromatic H, CH). Elemental analysis (CaDH31N03S> Calculated: C, 65.71; H, 8.55; N, 3.83; S, 8.77 Found: C, 65 · 65; H, 8.43; N, 3.85; S, 8. 78. Compound 9a: mp = 137-138¾. IRiKBricm-1: 3560,2975,1637,1600,1431,1289,1275, (Please read the precautions on the back before filling this page) -Packing. Standard (CNS) A4 specification (210 × 297 mm) 27 V. Invention description (26) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1168,1150, 1111. NMR (CDC13) 5; 1.26 (3H, t, J = 7.2Hz, CH3), 1.45 (18H.s, 2X Bu *), 3.00 (2H, dt, J = 2.0,6.0Hz, CH «), 3.15 (2H, q, J = 7.2 Hz, CHa), 3.25 (2H, t, J = 6.0Hz, CHa), 5.47 (lH, s, OH), 6.73 (1Η , J = 2.0Hz, CH), 7.52 (2H, s, 2x aromatic-H) · Wood element analysis (CaDH3iN〇3S) Calculated value: C, 65.71; H, 8.55; N, 3.83; S, 8.77 found : C, 65.68; H, 8.43; N, 3.61; S, 8.66 ¾J @ L2_ (R3 = CHa) (£) -2- 甲某 -5- (3.5- 二-笛 三 丁某 -4- 锊) Ya; -1.?-Li 1¾ _pyridine-1. 1-Diqifu. (8h) 苻 (Z) -Li suspect (Qh) In a similar manner as in Example 1, compound 6 (3.34 g, 12 mmol) and N-methyl-1,2-isopropazolidine-1,1-dioxide 4b (1.35 g, 10 moI) were subjected to aldol reaction to obtain 1.65 g (40%) of addition compound 7b . To a solution of the addition compound 7b (1.60 g, 3.87 mmol) in toluene (30b1) was added p-toluenesulfonic acid hydrate (160 mg), and the resulting mixture was heated to reflux for 30 minutes. The reaction products were subjected to column chromatography on a silica gel. From the fractions eluted with a mixture of n-hexane / ethyl acetate (3: 7), mesh 8b (580 mg > 43%) and 9b (200 mg, 15%) were obtained. Compound 8b: β.ρ. = 168-170Ό. IR (CHC13) cm-1: 3620, 2956, 1435, 1292, 1218, 1149. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 2.76 (3H , s, NCH3), 3.07-3.18 (2H, ffl, CHi), 3.20-3.32 (2H > iB, CH8), 5.51 (lH, s, This paper size applies to China National Standard (CNS) Α4 size (210X 297 (Mm) 28 (please read the notes on the back before filling this page) • Case · τ Γ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Invention Description (27) 〇H), 7.23-7.29 (3H, m, 2x aromatic-H, CH) _ Elemental analysis (C13HssN03S > Calculated value: C, 64.92; H, 8.32; N, 3.98; S, 9.12 贲 Estimated value: C, 64.62; H, 8.31; N, 3.95; S, 9-14. Compound 9b: ln.p. = 152-163¾. IR (CHCl3) cm-1: 3622,2956,1433,1293,1241,1160,1010. NMR (CDCU) S: 1.45 (18H, s, 2XBu ", 2.75 (3H, s, NCH3), 2.95-3.05 (2H, mF CH3), 3.16-3.26 (2H, m, CHa), 5.49 (1H, s, OH>, 6.75 (lH, t, J = 2.2Hz, CH), 7.58 (2H, s, 2x aromatic-H) Elemental analysis (Ci 3H »sN〇3S) Calculated value: C, 64.92; H, 8.32; N, 3.98; S, 9.12 Measured value : C, 64.61; H, 8.29; N, 3.95; S, 9.07. Sinus Example 3 (R3 = CH, CH (CH3) 2) (E) -2-M Ding -S- (3.5-di-ditributane-4-throw) cebenzyl-1. 2-isopyridine-1.1-diargon. In a similar manner as in Example 1, compound 6 (2.78 g, 19 miB0l) and N-isobutyl-1,2-isopropazolidine-1, dioxane 4c (1.95 g, 11 mmol) were subjected to aldol reaction to obtain 3.67 g (81%) of an addition compound 70 ° This addition compound 7c (3-60 g, 7.9 mol) was treated with toluene (50 weight 1) in a manner similar to Example 1 using p-toluenesulfonic acid hydrate (360ng). The product was subjected to a column on a silica gel The target compound 8c (1.30 g, 42%) was obtained from the fractions obtained by the chromatographic chromatography and the dissociation using a mixture of n-hexane-ethyl acetate (1: 3). This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 29 丨 ~ „--- ^ ---- ϊ— 装 ----- ^ 丨 Order ------ line (please (Please read the notes on the back before filling this page) V. Description of the invention (28) A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs mp = 167-170¾. IR (CHCl3) cnr1: 3620,2956, 1646, 1435 , 1289, 1240, 1148, 1081. NMR (CDC13) S: 0.97 (6H, d, J = 6.4Hz), (CH3) a), 1.45 (18H, s, 2x BuM, 1.81-2.02 (1H, b, CH), 2.87 (2H, d, J = 7.4Hz, CH8), 3.06-3.18 (2H, m, CHa), 3.22-3.33 (2H, b, CHa), 5.50 (lH, s, 0H), 7.23- 7.27 < 3H, m, 2x aromatic-H, CH). Analysis by CgaHaeNOaS: C, 67.14; H, 8.96; N, 3.56; S, 8_15 Found: C, 66.85; H, 8.99; N, 3.58; S, 8.11. 窨 Example 4 (R3 = cyclopropyl) (E) -2- 顼 propylm-5- (3.5-di-didibutan-4- 锊) benzylidene-1. 2-Li Fa _ -1. 1-Dioxin. (8H) In a similar manner to Example 1, using compound 6 (2_67g, 9.6 ββοΙ) and N-cyclopropyl-1,2-isopropazol- 1,1-dioxide 4d (1.29g, 8.0β · 〇1) was subjected to aldol reaction to obtain 3.09g (88%) of addition compound 7d. 7d (3.0g, 7 «〇1) was co-treated with toluene (50ml) using p-toluenesulfonic acid hydrate (300mg). The reaction product M was purified in a similar manner to Example 3 to obtain 1.03g (40%) mesh. Compound 8d. A. P. = 202-204V. IRiCHClaJcm1: 3620, 2956, 1434, 1297, 1237, 1145. NMR (CDC13) 5: 0.68-0.90 (4H, m, 2X CHe), 1.44 (18H, s, 2x Bu *) 2.28-2.40 (1H, m, CH), 3.08 (2H, dt, J = 2.6,6.7Hz, CH.), 3.36 (2H, t, J = 6.7Hz, CHS), 5.51 (lH, s, OH), 7.2〇-7.25 (3H, (Please read the precautions on the back before filling this page). Packing. Ordering Kang. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 30 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____________ B7 V. Description of the invention (29) m, 2x aromatic-H, CH) · Elemental analysis (CaiH31N〇3S) Calculated value: C, 66.81; H, 8.28; N, 3.71; S, 8.49 Found: C, 66.67; H, 8.29; N, 3.71; S, 8.38. Example 5 (R3 = CH2CH2CH3) (E) -2-TF · Bingmou-5- (3.5- 二- Di Sanding Mou-4-Wu) 昍 竽 Mou -1.2-Isopyridine-1.1-Diargonide (8e) »Its (7J-Li suspected in a similar manner to Example 1, using compound 6 (2. (78g, 10 BBol) and N-n-propyl-1,2-isopropazolidine-1,1-digas 4e (1.35g, 8.27ϋ · ο1) were subjected to aldol reaction to obtain 1.5g (41%) Addition compound 7e. Addition compound 7e was treated in a similar manner as described in Example 1 using p-toluenesulfonic acid hydrate (400 * g). The reaction product was subjected to column chromatography on a silica gel and the target compound 8e (810mg, 26%) and 9e (120mg * 3.8) were obtained from the fractions obtained by dissolving using a mixture of n-hexane-ethyl acetate (1: 4). %) 〇 Compound 8e: m. Ρ · = 181-183ΐ !. IR (CHCl3) cm-1: 3616,2954,1435,1289,1146. NMR (CDC13) δ: 0.98 (3H, t, J = 7.4Hz , CH3), 1.45 (18H, s, 2x BuM, 1.57-1.78 (2H, b, CHs), 2.98-3.20 (4H, b, 2x CHa), 3.22-3.34 (2H, m, 2x CHa), 5. 50 (1H, s, OH), 7.23-7.27 (3H, m, 2x aromatic-H, CH). Elemental analysis (CalH33N03S) * Calculated: C, 66_45; H, 8_76; N, 3.69; S, 8.45 Measured Value: C, 66.25; H, 8.74; N, 3.70; S, 8.33. This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -31-1 ^ --- ^ ----- -l · —Installation -----. 丨 Order ------ Line 1 (Please read the notes on the back before filling this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Β7 Ⅴ. Invention Explanation (3〇) Compound 9e: m · p. = 123-124. 5 ^ 0. IRiCHClaJcm-1: 3622, 2958, 1433, 1289, 1164. NMR (CDCla) 5: 0.96 (3H, t, J-7.4 Hz, CH3), 1.45 (18H, s, 2 x BuM, 1.55-1.72 (2H, m & g t; CHa), 2.95-3.08 (4H, m (2x CHa), 3.20-3.29 (2H, m, 2x CHa), 5.47 (lH, s, OH), 6.74 (lH, t, J = 2.1Hz, CH ), 7.57 (2H, s, 2x aromatic-H). Example 6 (R3 = 0CHa) (E) -2-methylargon-5-m-di-ditributane-4--4-) 1.2-Isoprazole-1.1-Difluorene > f. (8Π ^ qi (7J-Liquid (9f)) According to a similar method to Example 1, compound 6 (5. 56g, 20 Bmol) and N-methoxy-1,2-isoazosin-1,1-dioxide 4f (3.32 g, 22 mmol) were subjected to aldol reaction to obtain 6.89 g (80%) of an addition compound. Addition compound 7f (6.89 g, 16 mmol) in toluene (100 ml) was treated in a similar manner as described in Example 1 with p-toluenesulfonic acid hydrate (lg). The reaction product was subjected to column chromatography on silica gel and the fractions obtained by dissolving from a mixture of n-hexane-ethyl acetate (6: 1) to obtain the compound 8f (2.40g, 41%) and 9f (500mg, 8.5%). Compound 8f: mp = 166-168 ^. IRiCHClaJcm-1: 3616,2952,1639,1436,1340,1240,1158, 1002. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 3.11 (2H , dt, J = 2.8, 7.0Hz, CHS), 3.66 (2H, t, J = 7Hz, CHa), 3.81 (3H, s, 0CH3), 5.55 (lH, s, 0H>, 7.25-7.35 (3H, m, 2x aromatic-H, CH). Elemental analysis (C19HasN〇4S) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -32 _ ^ ^ _ ^ ^ --- order ----- -^ —1 (Please read the notes on the back before filling out this page) A7 B7 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (31) Calculated value: C, 62.10; H, 7.95; N, 3.81; S, 8.72 Found: C, 61.90; H, 7.88; N, 3.91; S, 8.67. Compound 9f: mp = 173-176Ϊ:. IR (CHCla) cn-1: 3616, 2950, 1431, 1341, 1240,1155,1010. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 3.12 (2H, dt, J = 2.2, 6.8Hz, CH2), 3.61 (2H, t > J = 6.8Hz, CHa), 3.61 (3H, s, 0CHa), 5.49 (1H, s, 0H), 7.01 (1H, t, J = 2.2Hz, CH), 7.49 (2H, s, 2x aromatic-H). Elemental analysis ( ClsHasNCUSX 〇.4HS0) Calculated value: C, 60.90; H, 8.02; N, 3.74; S, 8.56 Found: C, 61.08; H, 7.76; N, 3.75; S, 8.61. Fen example 7 (R3 = 0CHaC6He) (R) -2-benzylsulfonium-fi- (3.5-di-ditributane-4-fluorene) benzylidene-1.2-lipidin -1.1-Dimethyl compound (8g) According to a similar method to that in Example 1, using compound 6 (15g, 54 mmol) and N-benzyloxy-1,2-isosleepazidine-1, 4 g of dioxane ( 10.23 g (45 iamol) were subjected to aldol reaction to obtain 15.5 U (68%) of the addition compound 7 g. The addition compound 7 g (10.21 g, 20 — 2mnol) in toluene (150 ml) was used in a similar manner as described in Example 1 using p-toluene. Treatment with sulfonic acid hydrate (lg). The reaction product was filtered through a small amount of silica gel, and the filtrate was concentrated in vacuo to obtain 5.32 g (59%) of the target compound 8 g (B.P. = 134-135t :). IR (CHCl3> Cffl *: 3620, 2956, 1639, 1436, 1339, 1241, 1159 · NMR (CDC13) 5: 1.44 (18H, s, 2X BuM, 3.09 (2H, dt, J = 2.6, 6.8 Hz, CH.), 3.58 (2H, t, J = 6.8Hz, CHil), 5.02 (2H, s > 0CHa) > This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 33 I- ^ --- Λ--lL --------------- Order ------ line 1 (Please read the precautions on the back before filling out this page) V. A7 B7 Description of Invention (32) 5. 53 (1 H, s, OH), 7.25-7.45 (8H, m, 7x aromatic-H.CH) Elemental analysis (CaeH33N04S > Calculated value: C, 67.69; H, 7.50; N, 3_16; S, 7.23 Found: C, 67.52; H, 7.59; N, 3.18; S, 7.16. Real J @ LS_ (R3 = 4-methoxybenzyl) -Didibutan-4-fluorene) Benzylidene- 1.2-Li__ 腚 -1.1-Diargonide (8h) 苻 Its (Z) -isomer (9h) Following a procedure similar to Example 1, compound 6 (9g, 32MOL) and N- (4- Methoxybenzyl-1,2-isoprazidine-1, dioxane 4h (7.24g, 30miB0l) was subjected to aldol reaction to obtain 13.61g (84%) of addition compound 7h. Addition compound 7h (12.6g, 24.2β · ο1) in toluene (150ml) in a similar manner to Example 1 using p-toluenesulfonic acid hydrate (1.3 g) was processed to obtain 8.83 g of a mixture of mesh hydrazone compounds 8h and 9h.

Example 9 (113 = 3,4-Dimethoxybenzyl) (.V / 1-Nitrogen Argon ¥ Sodium) -5- (H -Disanbutane-4- 筠 (Please read the precautions on the back first (Fill in this page again) Binding and binding. -Quan _ Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Z) -Isomer (9i) According to a similar method to Example 1, using compound 6 (5.6 g, 20 mmol) and N- (3,4-dimethoxybenzyl) -1,2-isoxazolidine- 1,1-dioxide 4i (5.85 g, 21.6 mmol) was subjected to aldol reaction to obtain 9.25 g (78%) of addition compound 7i. Addition compound 7i (4 g, 7.3 mmol) M was subjected to dehydration and deprotection in a similar manner as described in Example 1 to obtain the eye-dwelling compounds 8i and 9i (2.5 g). 34 This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (33) Example 10 (R3 = CeH ») -5- (3.5-Second-Third Ding-Mou-4- 亚 1 Alkyl ny _ 腚 -1 · 1-Second-Serve (8.i) and Its (Z) -Li Suspect (9 "lI According to a similar method to Example 1, using compound 6 (2.47 g, 8.88 mmol) and N-phenyl-1,2-isothiazolidine-1,1-dioxide 4j (2.19 g, 11.10 mmol) Aldol reaction gave 3-184 g (75%) of addition compound 7j. Addition compound Ή (3.184 g, 6.69 mmol) in toluene (100 ml) was treated with p-toluenesulfonic acid hydrate (750 ml) to obtain the target. Compound 8j (667ng, 24%) and (110mg, 4%). Compound 8 _]: 1 ^?. = 195-196 < · IR (KBr) cm-1: 3560,3520, 2960,1636,1593,1492 , 1430, 1295, 1268,1105,1092. NMR (CDC13) (5: 1. 47 (18H, s, 2 x Bu *), 3.31 (2H, dt, J = 2.6, 6.6Hz, CH.), B .80 (2H, t, J-6.6Hz, CHa), 5.54 (lH, s, 0H), 7.17-7.26 (111,111, aromatic-11, (^>, 7.29 (2 [1,3,2 parent Aromatic-} 〇, 7.38 -7.42 (4H, m, 4x aromatic-fluorene). Elemental analysis C »« H3iN〇4SX 0 1H20 > Calculated value: C, 69.39; H, 7.61; N, 3.37; S, 7.72 Found: (:, 69.27; 11, 7.60; 13_39; 5, 7.61 · ^ (KBrJcm-1 : 3540, 2960, 1629, 1598, 1503, 1435, 1305, 1255, 1140, 1118. NMR (CDC13) 5: 1.44 (18H, s, 2X BuM, 3.17 (2H, dt, J-2.0, 6.2Hz , CHa), 3.77 (2H, t, J = 6.2Hz, CHs), 5.49 (lH (s, OH), 6.84 (lH, t, J = 2.0Hz, CH) 7.18-7.40 (5H, m, 5x Aromatic-H), 7.59 (Please read the notes on the back before filling this page) Binding-. The size of the original paper is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 35 5. Description of the invention (34

A7 B7 (2 Η 's, 2 X aromatic ~ μ) Elemental analysis ((^ 4ΐι3ιΝ〇35Χ〇 > 1Η80)) Calculated value: C, 69.39; H, 7.61; N, 3.37; S, 7.72 Found: C , 69.28; H, 7.56; N, 3.39; S, 7.69. 蓳 ^ 丄 (Ra = 4 ~ chlorophenyl) U di (3.5_di-ditributyrate-r bi) Wuwu-U2-isosia Azole ^ 1. 1. erbium (8k) is good (z) _ susceptible (9k) According to a similar method to Example 1, using compound 6 (2.25g, 8.09 mmol) and N- (4- Chlorophenyl) -1,2-isoprazidine-1,1-dioxide 4k (2.34 g, 10.1 mmol) was subjected to aldol reaction to obtain 2.54 g (62%) of addition compound 7k. Addition Compound 7k (2.53g, 4.96πηη〇1) was treated in toluene (70ml) with p-toluenesulfonic acid hydrate (250mg) to obtain the compound 8k (859mg, 39%) and 9k (263mg, 12%). 8k: mp = 245-246C. IRiKBricm-1: 3560,3960,1644,1592,1491,1430,1280, 1105,1090. NMR (CDC13) §: 1.46 (18H, s, 2x BuM, 3.30 (2H, dt , J = 2.6, 6.6Hz, CHa), 3.76 (2H, t, J = 6.6Hz, CHa), 5.55 (lH, s, 0H), 7.28 (213, aromatic-10, 7.26-7.40 (511, 〇 1,4 parent aroma- {1, (:} 1) · Elemental analysis (Ca4H3DN〇3SCl > Calculated value: C, 6 4.34; H, 6_75; N, 3.13; S, 7.16; C1,7.91 Found: C, 6459; H, 6 · 78; N, 3 · 28; S, 7 · 17; Cl, 7.87 · Compound 91 <: ffl.P · = 207-209cC. IRiKBricm-1: 3540, 2955, 1635, 1595, 1494, 1432, 1300,------------------------ Order-- --- Quan {(Please read the notes on the back before filling out this page) Printing policy of Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) -36-36

Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I A7 _B7 _ V. Description of Invention (35) 1270,1130. NMR (CDC13) 5: 1. 44 (18H, s, 2X Bu *), 3. 17 (2H, dt , J = 2.0, 6.4Hz, CHa), 3.73 (2H, t, J = 6.4Hz, CH *), 5.51 (1H, s, OH), 6.86 (lH, t, J = 2.0Hz, CH >, 7.34 (4H, s, 4x aromatic-H), 7.57 (2H, s, 2x aromatic-H). Elemental analysis (Ca4H3DN03SCl) Calculated value: C, 64.34; H, 6.75: N, 3.13; S, 7.16; CI, 7.91 Found: C, 6414; H, 6_80; N, 3.23; S, 706; C1, 7.95 XJ @ L1 ^ (R3 = 2-pyridyl) ^)-2- (2-pyridine and even) -5- (3.5-Second-Third Ding-Mou-4- 筠) Xishenxi-1.2-Lizhi Postidine-1.1-Difluoride (8Π 好 其 (7.)-蛊 suspect (Q Π similar to Example 1 Method: Compound 6 (208 mg, 0.75 mmol) and N- (2-Pttimidinyl) -1,2-isosleepazolidine-1, butadioxide (41) (149 mg, 0-75 mmol) were used for aldol The reaction yielded 233iog (65%) of addition compound 71. Addition compound 71 (231g, 0.485nunol) was treated with p-toluenesulfonic acid hydrate (60ng) in toluene (5ml) to obtain the head compound 81 (96mg, 48 %) And 91 (19 mg, 9%). Compound 81: mp = 177-179 ^ 0. I MKBrUnr1: 3570,2960,1646,1600,1587,1472,1431, 1300,1105,1085. NMR (CDC13) 5: 1.47 (18H, s, 2x BuM, 3.31 (2H, dt, J = 2.4, 6.8Hz, CHa), 4.08 (2H, t, J = 6.8Hz, CHa), 5.55 (1H, s, OH), 6.99-7.05 (lH, m, CH >, 7.28 (2H, s, 2x aromatic-H), 7.38 (lH, t, J = 2.4Hz, Py-H), 7.55-7.74 (2H, m, 2x Py-H), 8.33-8.36 (1H, 1J --- J ---- l · I-- ---.—— Order .------ Quan (Please read the notes on the back before filling out this page) V. Description of invention (36) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs m, Py -H). Elemental analysis (Ca3H3eNa〇3S) Calculated: C, 66.63; H, 7.29; N, 6.76; S, 7.73 Found: C, 66.31; H, 7.30; N, 6.72; S, 7.66. Compound 91 : mp = 198-199C. IRiKBrJcm-1: 3550,2960,1626,1594,1570,1470,1429, 1312,1302,1272,1140,1115. NMR (CDC13) 5: 1.46 (18H, s, 2x BuM, 3.16 (2H, dt, J = 2.0, 6.6Hz, CHa), 4.06 (2H, t, J-6.6Hz, CHa), 5.51 (lH, s, 0H), 6.87 (1H, t, J = 2.0Hz, CH), 6.96-7.04 (1H, m, Py-H), 7.58 (2H, s, 2x aromatic-H), 7.54-7.73 < 2H, b, 2x Py-H), 8.32-8.37 ( 1H, m, Py-H). Calculated analysis (Ca3H3DN * 〇3S) Calculated value: C, 66.63; H, 7.29; N, 6.76; S, 7.73 Found: C, 66.40; H, 7.23; N, 6.71; S, 7.53. Example 13 (R3 = 3-pyridyl) ") -2- (34-pyridinyl) -5- (3.5-bis-fluorene" Sandingmo-4- 某) 55 ¥ -1.2-Isophoridine-1.1-Diphenanthrene. The compound fRm was used in a similar manner to Example 1 using compound 6 (1.474g, 5_30mmol) and N- (3_ Pyridyl) -1,2-isonazosin-1,1 oxide 4m (1.051g, 5.30β »» 1) was subjected to an aldol reaction to obtain 1.522g (60%) of an addition compound 7m. Addition of 7m (1.522g, 3.19Bmol) of compound in toluene (40ml) was treated with p-toluenesulfonic acid hydrate (400mg) to give 358Bg (27%) of mesh VIII compound 8 .. This paper size applies to China National Standard (CNS) A4 specifications (210X297 male thin) 38 (Please read the precautions on the back before filling this page) t [A7

Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs. 5. Description of Invention (37) a. P. = 207-209Ϊ:. IRiKBrJcffl'1: 3625, 3040, 2960, 1640, 1590, 1480, 1431, 1305, 1152. NMR (CDC13) 5: 1.47 (18H, s, 2x BuM, 3.36 (2H, dt (J = 2.4.6.4Hz, CHa), 3.84 (2H, t, J = 6.4Hz, CHa), 5.59 (lH, s , 0H), 7.29 (2H, s, 2x aromatic-10, 7.29-7.40 (211, To, (:) 1 rush > ^) 〇, 7.84-7.93 (lH, m, Py-H), 8.37- 8.64 (2H, m, 2x Py-H). Element analysis (CaaHjjuNsOaS> Calculated value: C, 66.63; H, 7.29; N, 6.76; S, 7.73 Found: C, 66.31; H, 7.27; N, 6.69 ; S, 7.47 aL @ LLl (R3 = 4-pyridyl) (E) -2- (4_11Rinidine, S- (into di-di, ding shi-4-)) ¢ 5 ¥ -1.2- Isopyridine-1.1-diargonide (8η) Following a procedure similar to that described in Example 1, using compound 6 (2.59 g, 9.36 mmol) and N- (4-pyridyl) -1,2-isosleepazole Pyridine-1,1-dioxide 4n (2.05g, 10.4iBmol) was subjected to aldol reaction to obtain 2.721g (61%) of addition compound 7n. Addition compound 7n (1.65g, 3.46πμηο1) in toluene (80ml) Treatment with p-toluenesulfonic acid hydrate (433 mg) gave 658i »g (46%) of the mesh compound 8n. Bp = 213-214.5TC IRiKBrJcm-1: 3400,2955,1643,1591,1502,1437,1316, 1153. NMR (CDC13) 5: 1.47 (18H, s, 2x BuM, 3.37 (2H, dt, J = 2.2, 6.8Hz, CHa ), 3.82 (2H, t, J = 6.8Hz, CHa), 5.61 (lH.s, OH), this paper size applies to China National Standard (CNS) A4 specification (210X29 * 7 mm) 39 (Please read the back first Please fill in this page for the matters needing attention) • Send. V. Description of the invention (38 A7 B7 7.2, Bu 7.25 (411, Ling, 2 \ Aroma-11, 2 ??-1-10, 7.42 (111,1:, < 1 = 2.2 Hz, CH) I8.50-8.58 (2H, «, Py-H). CaaHaeNaOaS Calculated value: C, 66.63; H, 7.29; N, 6.76; S, 7.73 Test value: C, 66.46; H, 7.18; N, 6.66; S, 7.49. M〇m〇 (t-Bu, / t-Bu

0 S: 'N, 〇 I Y

7

(E / Z mixture) Take off guarantee iii (Ya = take off Bao Jiji) I 11 I n I n Thread (please read the precautions on the back before filling in, page r) Printed by Industrial and Consumer Cooperatives

(E-isomer) 10a

(Z-isocyanate) 10b (R3 = Η) (Υ = C0.C (CH3),) (Κ) -Η- (Di-Di San Ding Mou-4- 筠 V Xiwu Mou. 2-Li 臃ΡΦ 腚 1.1-Diargon servant. 物 now This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) -40-Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention ( 39) According to a similar method to Example 1, using compound 6 and N- (third butoxycarbonyl) -1,2-isopropazolidine_1 :: 1-dioxide 4O (which is composed of starting materials, 3-Chloropropylsulfonium and tertiary butyl carbonate are prepared according to Reaction Scheme 1) Aldol reaction is performed to obtain a crude addition compound 70. To the solution of the crude addition compound 70 in toluene, p-toluenesulfonic acid is added. The hydrate and the resulting mixture were heated to reflux for 45 minutes, and then subjected to column chromatography on a silica gel. The target compound 10a was obtained from the fractions using a mixture of n-hexane / ethyl acetate (2: 1). Yield 8.5%). M · ρ. = 233-234Ϊ: · IR (CHCl3) cm-1: 3618,2952,1435,1366,1311,1240,1155, 1070. NMR (CDC13) 5: 1.45 (18H, s, 2X Bu *), 3.18 (2H, dt, J = 2.6, 6.8Hz, CHa), 3.42 -3.60 (2H, m, CHs), 4.05-4.25 (1H, wide, NH), 5.52 (1H, s, 0H>, 7.22-7_ 27 (3H, m, 2X aromatic-H, CH) Elemental analysis (CieHa7N03Sx 0.35HsO) Calculated value: C, 62.89; H, 8.12; N, 4.07; S, 9.38 Found: C, 63 · 10; H, 7.90; N, 417; S, 9_ll; j £ _ ®lJ ^ (R3 = H〉 (Y = 4-methoxybenzyl group> (Z) -fi-f di-ditributane-4--4-)) ·:!-Dihydrogenate. Π Oh) To the addition compound 7h (13.16g, 25.3nnol) (M obtained by the aldol reaction in a manner similar to Example 8) p-toluene was added to a solution of toluene (150ml). Sulfonic acid hydrate (1.3g). The resulting mixture was heated to reflux for 30 minutes and filtered through a small amount of silica gel. The filtrate was distilled. This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) 41 (Please read the precautions on the back before filling this page). Binding. Order five. Invention Description (4〇) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs to remove dissolved rain to obtain rough (E > -and (Z > -2- (4-methoxybenzyl) -5_ (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isosiazolidine-1,1-dioxide 8h and 9h mixture (8.93g). To a solution of digas methane (150 ml) was added titanium tetragas (4.1 ml). The resulting mixture was stirred at 0 for 30 minutes, and then subjected to column chromatography on a silica gel. Compounds 10a (3.35 g, 41%) and 10b (120 mg, 1.5%) were obtained from the fractions eluted with a mixture of n-hexane / ethyl acetate (1: 1). The physical and chemical data of Compound 10a corresponded to the actual sample data obtained in Example 15. Compound 10b: mp = 161_164t !. IRCCHClaicm-1: 3620, 2954, 1432, 1371, 1312, 1241, 1157. NMR (CDC13) 5: 1.45 (18H, s, 2X BuM, 3.ll (2H, dt, J = 2.1, 6.71 ^, (: ^, 3.39-3.51 (211,11, (: 11,), 4.26-4.40 (111, width, 1 ^), 5.49 (lH, s, 0H), 6.80 (lH, t , J = 2.lHz.CH), 7.55 (2H, s, 2x aromatic-H). Elemental analysis (CieHS7N〇3S) Calculated value: C, 63.72; H, 8.08; N, 4.13; S, 9.45 Found: C, 63.64; H, 8.14; N, 4.06; S, 9.36. Example 17 (R3 = Η) (Y = 3,4-dimethoxybenzyl) in addition compound 7i (4_0g, 7.3nmol) (in Obtained from the aldol reaction of Example 9) To a solution of xylene (50b1) was added an equivalent amount of 2,6-di-tert-butylphenol, anisole and p-toluenesulfonic acid hydrate. The resulting mixture Heat to reflux for 45 minutes and undergo column chromatography on silica gel to obtain compounds 10a (580mg, 24%) and 10b (85®g, (please read the precautions on the back before filling in this f) -Pack.,-· *-泉 i- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 42 5. Description of the invention (41) A7 B7 3.5%). Physical data of compounds 10a and 10b Minute Examples 15 and 16 in line with real income of the sample data.

t- 巳 u alkylation hydrazine amine methylation oxocarbonylation 〇 、, 〇 Base (D)

(E / Z) 8J 10 Example 18 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (R3 = CUCD (R) -2-Z. Qi Di Shen Shen -5- (3.5-II-Di San Ding Shi- 4-Vacuum) Xihanmou -1 Li Xing Pyridine-1.1-Difluoride (8d) (E) -5_ (3,5-Di-tertiary-butyl-4-hydroxy) benzylidene-1 , 2-Isoprazole-1,1-dioxide 10a (500mg, 1.48dmbo1), ethyl iodoacetate (240til, 2mm0l), 2N sodium hydroxide (1.5β1, 3ιββο1) aqueous solution and Children's N-benzyltrimethylammonium chloride was sequentially added to a mixture of chloroform (20ml) and water (10βΙ). The resulting mixture was stirred at room temperature for 24 hours and then treated in a conventional manner. The product was borrowed on silica gel Purified by column chromatography to obtain 300 mg (49%) mesh compound 8P. IR (CHC13) cib-1: 3620,2956,1747,1435,1298,1229,1160. NMR (CDC13) 5: 1.29 (3H, t , J = 7.2Hz, CH3), 1.45 (18H, s, 2 x BuM, 3.19 (2H, dt, J = 2.6,6.6Hz, CHa), 3.51 (2H, t, J = 6.6 Hz, CH «), 3.87 (2H, s, CHaC0), 4.23 (2H, q, J = 7.2Hz, CHa), 5.5_2 (lH, s, 0H〉, 7.22-7.30 (3H, ra, 2x aromatic-H, CH) (Please (Please read the notes on the back before filling this page) Standard (CNS) A4 (210X 297 mm) 43 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (42) Example 19 (R3 = CHaCOOH) (fp-9- 杂 申 某- 5- (3 · 5-Di-Third Ding Mou-4-Wu) Yawu Mou-U-Sound Beer η $ -1 · 1-Diargon. Compound (8α) Compound 8p (610mg, 1 44mmol) (As obtained in a manner similar to Example 18) and 2N-sodium hydroxide (1.5 ml) was added to a mixture of THF (IObI) and methanol (4 nl). The resulting mixture was stirred at 01 for 30 minutes. After adding ethyl acetate (50 ml) The reaction mixture was washed with HCl aqueous solution (20b1) and saturated brine (20ml), dried over MgSO4, and the solvent was removed by vacuum distillation to obtain 445mg (78%) of the compound 8q (mp = 175-1781). IRiCHCUjca-1: 3620,2954,1735,1435,1297,1240,1149. NMR (CDC13) 5: 1.45 (18H, s, 2x Bu *), 3.20 (2H, dt, J = 2.6, 6.6Hz, CHa), 3_51 (2H , T, J = 6.6Hz, CH *), 3.95 < 2H, s, CHaC0), 5.54 (lH, s, 0H), 7.25 (3H, s, 2x aromatic-H). Elemental analysis (CaDHasN0eS > calculated value : C, 60.46; H, 7.41; N, 3.53; S, 8.07 Found: C, 60.34; H, 7.40; N, 3.56; S, 8.04. Example 20 (R3 = CHaCHa〇H) (E) -2- (2-hydroxyethyl) -5- (· υ-di-di = dibutrazol-4- 镩) -1.1-Diargon (8rO compound 10a (675mg, 2anaol), 2-iodoethanol (624 < il, 8 mmol), 2N-sodium hydroxide aqueous solution (2ml) and a small amount of N-benzyl chloride Methyl ammonium was added to a mixture of dichloromethane (20 ml) and water (10 »1). The resulting mixture was heated to reflux for 3 days and treated in a conventional manner. The product ___ shouted: 厶 j This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) -44— * 1 (Please read the back Note: Please fill in this page again.) • Binding, binding, spring, and printing of A7 B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (43) Column chromatography was performed on silica gel. From the fractions eluted with a mixture of n-hexane / ethyl acetate (7: 3), 190iag (25%) of the mesh compound 8r (mp = 156-1570. IR (CHC13) ci-1: 3620, 2950, 1434 , 1290,1240,1151,1066. NMR (CDC13) S: 1.45 (18H, s, 2x BuM, 3.16 (2H, dt, J = 2.4, 6.5Hz, CH «), 3.30 (2H, m, CHa), 3.41 (2H, t, J = 6.5Hz, CHa), 3.87 (2H, t, J = 5.2Hz), 5.53 (lH, s, OH), 7.23-7.29 (3H, m, 2 X aromatic-H, CH 〉. Elemental analysis (CsdH31N04S > Calculated value: C, 62.96; H, 8_19; N, 3.67; S, 8.40 Found: C, 62.72; H, 8.27; N, 3.69; S, 8.21. Example 21 (R3 = CH * CH, N (CH3) e) (FJ-2- (2-dimethylamine, even Z, etc.)-5- Π.5-di-didibutane-4- 狰) benzylidene-1.2- Pyridoxine-1. Dipyridine (8s) Compound 10a (843mg, 2-5mBol), N, N-dimethyl-2-moethylamine (750mg, 5minol), 2N-sodium hydroxide aqueous solution ( 3nl, 6hbo1) and a small amount of N-benzyltrimethylammonium chloride were added to a mixture of chloroform (30ml) and water (10ml). The resulting mixture was stirred under ice-cooling for 2 hours. The aerated layer was washed with water (20mix2) And M anhydrous sodium sulfate. The solution was vacuum steamed to remove aerosol, 950 mg (93%) of the compound of eye mesh was a crystalline residue (mp = 160-16510). IR (CHCl3) cm-1: 3620, 2956, 1435, 1290, 1148. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 2.29 (6H, s, N (CH3) a) 2.60 (2H, t, J = 6.6Hz, CHa), 3.12 (2H, dt, J = 2.2,6.6Hz, CH *), (Please read first Note on the back side, please fill in this page again). Binding · -The size of spring paper is applicable to China National Standard (CNS) A4 (2) OX297 mm

A7 B7 V. Description of the invention (44 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 3.20 (2H, t, J = 6.6Hz, CHa), 3.38 (2H, t, J = 6.6Hz, CHa), 5.51 (111, 3,01〇, 7.2, 7.28 (Beijing, 111, 2) < Aromatic 4, (:) 〇 Elemental analysis (CaeH36Na03SX 〇2CHaCla) Calculated value: C, 62.65; H, 8.62; N, 6.58; S, 7.53; C1, 3.33 found: C, 62.32; H, 8.60; N, 6.71; S, 7.56; C1, 3.24. Sinus example 22 (R3 = COCH3) (E) -2-ethenyl-5- m- Bis-ditributane-4- 筠) Benzene-1.2-trimethylpyridine-ll-diargon. FXt, compound 10a (585mg, 1.74iomol) in pyridine (10ml) and a small amount To the solution of 4-N, N-dimethylaminopyridine was added dropwise acetic anhydride (6ml) under ice cooling. The resulting mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution Filtered through a small amount of silica gel 2. The filtrate was concentrated in vacuo to give 360 mg (55%) of the mesh compound as a crystalline residue (m_P. = 177-179C). IMCHCMcnr 1: 3618, 2958, 1695, 1435, 1379, 1297,1153, 1117. NMR (CDC13) 5: 1.46 (18H, s, 2x BuM ^ BOH.s.COCHa), 3.20 (2H, dt, J = 2.2,7.0Hz, CHa), 3.86 (2H, t , J = 7.0Hz, CHa), 5.60 (1H, s, 0H), 7.52 (2H, s, 2x aromatic-H>, 7.39 (lH, t, J = 2.2 Hz, CH). Elemental analysis (CaDHa9NCUS) Calculated value: C, 63.30; H, 7.70; N, 3.69; S, 8.45 Measured values: C, 63.27: H, 7.83; N, 3.64; S, 8.22. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297) PCT) (Please read the precautions on the back before filling this page).

1T-Quan A7 B7 Consumption Cooperation by Employees of the Central Government Bureau of the Ministry of Economic Affairs 5. Printing of the Invention (45) Fen Li 23 (R3 = N-methyl-N-methoxy) fPU- ( ) Amine application -5--5- di-di = Ding -4- 锊) sub- ¥ -1.2-si-pyridine-1.1-dihydrazone (8υ) compound 10a (450mg, 1.33βμπο1) and N-formyl -N-methoxy-0-phenylcarbamate (300 mg, 1.66 mmol) was dissolved in a mixture of THF (10 fields 1) and HMPA (10 ml). Add hexamethyldisilazane (LiHMDS) in THF (1M, 3.2 1) dropwise into the solution with stirring and cooling to -40 ° C. The reaction solution was warmed to room temperature and poured into a 1N aqueous hydrochloric acid solution (20 ml). The mixture was then extracted with ethyl acetate (30 nl). The ethyl acetate layer was washed with water (30 ml) and saturated brine (30 nl), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was subjected to column chromatography on a silica gel. The title compound 8u (230 mg, 41%) was obtained from the eluted fraction using a mixture of n-hexane / ethyl acetate (7: 3). IR (CHC13) cid-1: 3620,2958,1673,1435,1388,1330,1240, 1207,1155,1092. NMR (CDC13) 5: 1.45 (18H, s, 2x Bu *), 3.21 (2H, dt , J = 2.2, 6.8Hz, CHa), 3.31 (3H, s, 0CH3), 3.78 (3H, s, 0CH3), 3.89 (2H, t, J = 6.8Hz >, 5.54 (lH, s, 0H), 7.23 (2H, s, 2x aromatic-H), 7.31 (1H, t, J = 2.2Hz, CH). Fen example 24 (R3 = N-benzyloxy-N_methoxymethyl) (R) -2- (N-benzyl argon-N-methyl argon phenoxide) amine sterilization -5- (3.5-di-tertiary butyl-4-fluorene) yamou-1.2-Lifa_pyridine-1.1-diqi (8v) Compound 10a (424mg, 1.26minol) and N-Betyloxymethyl-0-phenylcarbamate (722mg, 2.52mmol) in THF (90ml) This paper is in accordance with Chinese national standards ( CNS) Α4 specification (210 × 297 mm) -47: ----------- L--loading ----- ^-order ------ Travel (Please read the note on the back first Please fill in this page again) Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Mixture of Invention Description (46) and HMPA (300ml) M. Similar to the method described in Example 23, LiHMDS was used in THF (1M, 4.0 · 1). ) Solution treatment. The reaction product was subjected to column chromatography on silica gel. By using n-hexane / acetic acid The eluted fraction of the mixture of ethyl esters (3: 1) yielded 8v (600mg, 90%) of ocular habitat compound. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 3.18 (2H, dt, J = 2.0) , 6.8Hz, CHa), 3.45 (3H (s, NCH3), 3.79 (2H, t, J = 6.8Hz, CH.), 4.94 (2H, s, 0CHa), 5.02 (2H, s, 0CH #), 5.54 (lH, s, OH), 7.22 (2H, s, 2x aromatic-H), 7.30 (lH, t, J = 2.0Hz, CH >, 7.30-7.55 (5H, n, 5X aromatic-m. 25 (R3 = C0NH0H) (e) -2- (Zenamine formamidine) -s- (3.5-di-di-dine-4- 镡 i ro benzyl-1.2-li__ 腚 -1.1-two Compound M (8W). In a solution of compound 10v (600mg, 1.13mmol) obtained in Example 24 in dichloromethane (8ml) was added titanium tetrachloride (500W1, 4.56ββο1) under ice cooling, and the resulting mixture was stirred. 1.5 hours. After adding 2N hydrochloric acid aqueous solution (10 ml), the reaction mixture was stirred at room temperature for 30 minutes and then extracted with dichloromethane (20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was subjected to column chromatography on silica gel. 8w (150mg, 33%) was obtained from the fractions eluted with a mixture of n-hexane / ethyl acetate (1: D mixture). IR (CHCl3) cm-1: 3618, 2956, 1707, 1434, 1320, 1151,1100. NMR (CDCla) 5: 1.45 (18H, s, 2x BuM, 3.23 (2H, dt, J = 2.2, this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) bismuth Quit »Smoke 48-

Ia -------- L--install ------ order ------ mother (please read the notes on the back before filling this page) i. Description of invention (47 A7 B7 7.0Hz , CHa), 3.94 (2H, t, J = 7.〇Hz, CHa), 5.61 (lH, s, OH), 6.85-6.95 (11 wide, 01〇, 7.24 (2 {], 3, 2 > < Aromatic-} 〇, 7.30 (111, t, J = 2.2Hz, CH), 8.61 (1H, s, NH). Example 26 π,-?-镩 -5-gate. 5-Di-Third A certain 4-volume) benzyl-1. 2-Li _ _ -1 dihelium (11a) and its (Z) -Li 馋 Mlh)

(Please read the precautions on the back before filling out this page)-Discard · 欹 Ｍ Take off protection

11a, 11b, vs_ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs According to Example 1, compound 6a and N-benzyloxy-1,2-isosleepazolidine-1, 1-dioxide were used for the aldol reaction. The addition compound obtained by the aldol reaction was treated with p-toluenesulfonic acid hydrate to obtain crude 2-benzyloxy-5- (3,5-di-third-butyl-4-hydroxy) benzylidene-1,2 -Isoprazole-1, dioxane. In a solution of crude dioxide (4-44 g, 10 moiol) in dichloromethane (80 ml), titanium tetrachloride (4.4 ml, 40 ° C. was added dropwise with ice-cooling and stirring. After stirring for 2 hours at the same temperature, Add IN aqueous hydrochloric acid solution (50ml) to the reaction mixture. Dichloromethane, M water (50ml) and this paper size are applicable to China National Standard (CNS) A4 specifications (210X297 mm). Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print A7 __ 1 'Explanation of the invention (48) Wash with saturated brine (50ml), dry with anhydrous sodium sulfate and remove the solvent by vacuum distillation. The residue was subjected to column chromatography on silica gel. By using n-hexane / ethyl acetate (3: 1) The eluted compound lib (178mg, 5%) and 11a (1.6g, 45%) were obtained in the dissolving fraction of the mixture. Compound 11a: mp = 177-18210 (decomposed) IRiKBrJcm-1: 3560,3430,1425,1330,1240,1155,1130, 1115. NMR (CDC13) 5: 1.45 (18H, s, 2X BuM, 3. 18 (2H, dt, J = 2.6, 6.8Hz, CHa), 3.89 (2H, t, J = 6.8Hz, CHa), 5.56 (lH, s, 0H), 6. 18-6.30 (1H, wide, OH), 7.26-7.35 < 3H, m, 2x aromatic-H, CH >. Elemental Analysis (Ct eH8TN04S Calculated: C, 61.16; H, 7.70; N, 3.96; S, 9.07 Found: C, 6086; H, 7.68; N, 3.93; S, 8.90 · Compound llb: mp = 190-198cC (decomposition) IR (CHCl3) cin-1: 3622,3540,3020,2954,1632,1431,1340, 1241,1157. NMR (CDC13) 5: 1.45 (18H, s, 2X BuM, 3.17 (2H, dt, J = 2.2 , 6.8Hz, CHB), 3.62 (2H, m, CH8), 5.51 (lH, s, OH), 6.22 (lH, s, 〇H), 7.04 (lH, t, J = 2.2Hz, CH), 7_49 (2H, s, 2x aromatic-H) Elemental analysis (Q eHa7N0 «S > Calculated: C, 60.16; H, 7.70; N, 3.96; S, 9.07 Found: C, 60.67; H, 7.58; N, 3.96 ; S, 8.87. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) -50-IJ --- ^ --- JL--installation ------ order ----- -Brigade (please read the precautions on the back before filling this page) A7 B7 V. Description of the invention (49 啻 27 (R) -2-Isopropyl-5- (3 · 5- 二-三 丁丁- 4-throw, Yaqian-1-2_ 里 曈 Postidine-Ι.Ί- 二 argon servant. 8x

CHO 〇χγ〇 +

LDA

OH

p-TsOH 〇, / 〇

----- ^ ----- L--install ------ order ------ Af (Please read the notes on the back before filling this page) Ministry of Economic Affairs Central Standard _ Bureau employee consumption Cooperative prints a similar method according to Example 1 using N-isopropyl-1,2-isoisoprazole-1, dioxane < 4p > (3.65g, 22.4mmol) and 3,5-di- Tributyl-4-methoxymethoxybenzaldehyde (6a) (5.28g, 19.0mniol) was subjected to an aldol reaction to obtain 6.27g (74.7%) of the addition compound < 7p) as a white powder. To a solution of the addition compound 7p (6.27 g) in toluene (120b1) was added p-toluenesulfonic acid hydrate (600 mg). The mixture is heated to reflux. This paper is sized for China National Standards (CNS) A4 (210X 297 mm).

MiFET -51 Printed by A7 B7, a member of the Central Bureau of Associate Bureau of the Ministry of Economic Affairs, and Consumer Cooperatives — ~ -—------------ V. Description of the invention (50) 30 minutes, cool, wash with water (100ml) for two Then, it was dried over anhydrous sodium sulfate and evaporated under vacuum to remove solvent. The crystalline residue was recrystallized from methanol to obtain 2.16 g (30%) of the mesh compound as colorless crystals. Compound 8 \: 1 ».?. = 148-15〇 · ^ IRiKBrJcm'1: 3550, 2960, 1645, 1600, 1432, 1273, 1173. NMR (CDC13) 5 ·· 1.29 (6H, d, J = 6.6Hz, 2x CH3), 1.45 (18H, s, 2X BuM, 3.07-3. 14 (2H, m, CHa), 3.29 ~ 3.35 (2H, m, CH8), 3.94 < 1H, family, CH), 5.48 (lH, s, OH), 7.22 (lH, t, J = 2.8Hz, CH), 7.23 (2H, s, Ar-H). Elemental analysis < CaiH33N03S) Calculated value: C, 66.45; H, 8.76 N, 3.69; S, 8.45 Found: C, 66.37; H, 9.01; N, 3.67; S, 8.28. Fen Example 28 (1 ^ -9-7. -锊) subbenzyl-1.2-Li favors spleen-ll-digas (8y)

The size of this paper applies to China National Standard (CNS) Α4 specification (210 X 297 mm) ----------- L--packing ------ order ------ Λ. (Please (Please read the notes on the back before filling out this page) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A similar method according to Example 1 was used with N-ethyl-1,2-isopropazolidine-1, dioxane (4a) (2.5g, 16.8ππηο1) and 3,5-dimethyl-4-formaldehyde. Olg (77.8%) addition compound (7q) was a white powder. The oxymethoxybenzaldehyde (6b) (2.92 g, 15 mmol) was subjected to an aldol reaction. To a solution of the aldehyde fermentation compound 7q (3.75 g, 10.9 μm βο1) in toluene (100 · 1) was added p-toluenesulfonic acid hydrate (200 mg). The mixture was heated to reflux for 30 minutes. The reaction mixture was cooled, washed twice with M water (100 ml), dried over anhydrous sodium sulfate and evaporated under vacuum to remove the solvent. The crystalline residue was recrystallized from methanol to obtain 1.63 g (53%) of the mesh hydrazone compound as colorless crystals. Compound 8y: mp = 167-168t !. IR (Nujol) cm-1: 3399,1641,1593,1489,1461,1272,1217, 1170, 1145,1128. NMR (CDCla) 5: 1.29 (3H, t, J = 7.4Hz, CH3), 2.26 (6H, s, 2x CH3), 3.05-3.36 (6H, m, 2x CHs, NCHa >, 5.00 (1H, width, OH), 7.04 (2H, s, Ar-H ), 7.15 (lH, t, J-2.8Hz, CH). Elemental analysis (C14H13N03S) Calculated value: C, 59.76; H, 6.81; N, 4.98; S, 11.39 Found: C, 59.56; H, 6.85; N, 4.99; S, 11.38. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) ----- ^ ---------------- ---- Kang (Please read the precautions on the back before filling this page) Zhan Bu, ::. 'Dou Yue Yue Ί > 88. 8. 25 Bu Wu 1 A7 B7

CHO 〇, 々〇 + ^ N-Et

OH

V. Description of the invention (52 啻 29 (| ^ -9-7. Even-5- (3.5--diisopropyl--4- 瘅)) ¥ -1.2-Li 噱 睥 if -1. 1- Diargon (87) 4a. P-TsOH ^ ——M ----- pack— (Please read the precautions on the back before filling ^ 4 苋)

Printed by Shellfish Consumer Cooperative of Central Bureau of Quasi-Economics of the Ministry of Online Economics According to a similar method as in Example 1, N-ethyl-1,2-isosiazolidine-1,1-dioxide (4a) (4.9g, 32 8.β? 1) and 3,5-diisopropyl-4-methoxymethoxybenzaldehyde < 6c) (7.51g, 30aaOl) were subjected to an alcohol reaction to obtain 6.07g (50.6%) of an addition compound (7r) White powder. To a solution of the addition compound 7r (5.0 g, 200 mol-) in toluene (100 ul) was added p-toluenesulfonic acid hydrate (200 ng). The mixture is heated to the back. The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) -5 4-A7 B7. 5. Description of the invention (53) Flow through for 30 minutes. The reaction mixture was cooled, washed twice with M water (100 ml), dried over anhydrous sodium sulfate and evaporated under vacuum to remove the solvent. The crystalline residue was recrystallized from methanol to obtain 3.24 g (48%) of the mesh compound 8ζ as colorless crystals. Compound 8ζ: η · ρ. = 167-168t :. IR (Nujol) cm-1: 3413,1644,1600,1472,1276,1194,1153, 1115. NMR (CDCla) 5: 1.27 (12H, d, J = 6.6Hz. 2X CH (CH3) a), 3.06 -3.36 (8H, ib, 3x CH..2X CH), 5.13 (lH, s, 0H), 7.12 (2H, s, Ar-H), 7.24 ( 1H, t, J = 2.8Hz, CH). Element analysis (CieHa7N03S> Calculated value: C, 64.06; H, 8.07; N, 4.15; S, 9.50 Found: C, 64.03; H, 8.02; N , 4.11; S, 9.46. Fen example IE) -2-7. Even-R- (二 申 氲 -il- 镩) 55 benzyl-1. 2-Li favored PΦ ^ LJ di-diargide fRTd —ί- ---; —, —_-- install ------ order ------ Λ (Please read the notes on the back before filling this page)

Printed by MeO Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs

.CH〇 ΜΟΜΟ ^ γ 〇Me Μ +

N-Et 4a.

LDA This paper size rhyme nn house standard (CNS) 8 4 specifications (21Gx 297 public envy) A7 B7

0H

ZS_ V. Description of the invention (54

p-TsOH

MeO

OMe m According to a similar method as in Example 1, N-ethyl-1,2-isopropazolidine-1,4-dioxane (4 &) (5.22, 3511111〇1) and 3,5-dimethoxyl were used. -4-methoxymethoxybenzaldehyde (6 < 0 (6.77 g, 30mnol)) was subjected to aldol reaction to obtain 8.42 g (74.8%) of the addition compound (7s) as a white powder. The aldol addition compound 7s (4.28 g, 11.4 ... 1) To a solution of toluene (100 ml) was added p-toluenesulfonic acid hydrate (200 Bg). The mixture was heated to reflux for 30 minutes. The reaction mixture was cooled and washed with water (100 ml). Twice, dry with anhydrous sodium sulfate and remove the solvent by vacuum distillation. The obtained crystalline residue was recrystallized from methanol to obtain 1.64 g (46%) of the compound 81 a as colorless needles. Compound 81a ·· mp = 164-1661 ^. IRCNujoDcm1: 3434,1643,1607,1593,1517,1454,1321, 1273,1251,1219,1172,1149,1109. This paper size applies to China National Standard (CNS) A4 specification (2 丨 0'〆297 public) (Li) 丨 _ 丨 --- ^ --- 1--installation ------ order ------ into (please read the precautions on the back before filling out this page) Employees of the Central Bureau of Standards of the Ministry of Economic Affairs Cooperative printed A7 B7 (55) NMR (CDCla) 5: 1.30 (3H, t, J = 7.4Hz, CH3), 3.10-3.37 (6H, m, 3X CHa), 3.92 (6H, s, 2X 0CH3) , 5. 76 (1H, s, OH), 6.65 (2H, s, Ar-H), 7.20 (1H, t, J = 2.8Hz, CH). Elemental analysis (C14H13NOeS> Calculated value: C, 53_66; H , 6.11; N, 4.47; S, 10.23. Found: C, 53.45; H, 6.06; N, 4.44; S, 10.33. Examination example. Ή (FJ-2-Z, M-fi- ( 4-Wave) Fei ¥ -1-2. 2-¾ Favor _ Pyridine-1. 1-2 氤 servant, thing (8 Tb) (Please read the precautions on the back before filling this page)-equipment_

CHO

V

LDA + N-Et 4a.

, 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of Pan Department

OH

p-TsOH trip

57 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

i 'Explanation of the invention (56) According to a similar method to Example 1, N-ethyl-1,2-isosiazolidine-1, dioxane 4a (5.00g, 33.5anol) and 3-methoxy-4 were used. -Methoxymethoxybenzaldehyde (6e) (5.88 g, 30 mmol) was subjected to aldol reaction to obtain 4.35 g (42%) of the addition compound 7t as a white powder. To a solution of the aldol addition compound 7t (4.30g, 12.4 · βο1) in toluene (100al) was added p-toluenesulfonic acid hydrate (200mg). The mixture was heated to reflux for 30 minutes. The reaction mixture was cooled, washed twice with water (200 ml), dried over anhydrous sodium acetate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel. The eluate separated by n-hexane / ethyl acetate (2: 1) was separated and recrystallized from a mixture of methane / diisopropyl ether to obtain 2.7 g (31.8%) of the title compound as colorless crystals. Compound 81b: mp = 146-14813. IRCNujoDcm-1: 3404,2924,1646,1611,1594,1516,1462, 1270,1149,1130. MMR (CDC13) 5: 1.29 (3H, t, J = 7.4Hz, CH3), 3.08-3.18 (2H, m, CH »), 3.17 (2H, q, J = 7.4Hz, 2x CHa) (3.26-3.34 (2H, ni, CHs), 3.92 (3H, s (0CH3 ), 5.88 (lH, s, OH), 6.86-7.02 (3H, m, Ar-H), 7.21 (1H, t, J = 2.8 Hz, CH). Elemental analysis (C13H17N04S) Calculated value: C, 55.11; H, 6.05; N, 4.94; S, 11.32 Found: C, 54 · 75; H, 6.11; N, 4.99; S, ll23 £ _ @ Li2 (E) -2-Z even- .R- U- 镡) ¥¥ -1.2-Li suspected_disease--1,: 1-digas (8Tr >) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ^- ----- Ί--Equipment ------ Order ------ Brigade (Please read the notes on the back before filling out this page} Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A7

i 'Invention note (57)

--- „---- ^-i ---- pack ------- order (please read the notes on the back before filling this page) According to the similar method of Example 1, use N-ethyl- 1,2-Isosiazolidine-1, dioxane 4a (3.28g, 22miBOL) and 4-methoxymethoxybenzaldehyde (6f) (3.32g, 20mmol) were subjected to aldol reaction to obtain 4.10g (65%) Addition compound 7u was a white powder. To a solution of the aldol addition compound 7u (4.00g, 12.7bbo1) in toluene (ΙΟΟίΒ) was added p-toluenesulfonic acid hydrate (200ng). The mixture was heated to The reaction was carried out for 30 minutes. The reaction mixture was washed twice with water (200 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to column chromatography on silica gel. N-hexane / ethyl acetate (3: 2) was used. ) The dissociated fraction is separated and printed by dichloromethane and the paper size to apply Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Ministry of Tourism Economy, Central Labor Bureau, Consumer Consumption Cooperative. A7 B7 diisopropylene was recrystallized to obtain 1.0 g (31.1%) of the mesh compound as colorless crystals. Compound 81c: β · ρ · = 135-138T :. IRiNujoDcm1 : 3346,2914,1646,1605,1584,1513,1453, 1376,1282,1223,1136. NMR (CDC13) §: 1.29 (3H, t, J = 7.2Hz, CH3), 3.04-3.12 (2H,, CHO, 3.17 (2H, q, J = 7.2Hz, CHa), 3.27-3.33 (2H, m, CH a), 5.59 (lH, s, 0H), 6.85-6.90 (2H, m, Ar-H ), 7.19 (1H, t, J = 2.8 Hz.CH), 7.24-7.30 (4H, m, Ar-H). Elemental analysis (ClaHieN03S> Calculated value: C, 56.90; H, 5.97; N , 5.53; S, 12.66 Found: C, 56.74; H, 5.98; N, 5.52; S, 12.41. Fenyu (ugly) -2- (3.5-di-Di Sanding Mou-4-wave 1 £ 5 noon荖 顼 丁 打 (81 (^ Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

CHO V / °

LDA I.. —-Book I Trip (Please read the notes on the back before filling this page) +

〇H

〇

p-TsOH s This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 ~ __B7 V. Description of the invention (59)

Aldehyde was performed according to a similar method as in Example 1 using cyclamidine 4q (2.4g, 20mi »0l) and 3,5-di-tertiarybutyl-4-methoxymethoxybenzaldehyde 6a (5.57g, 20 ββοΙ). The alcohol reacted to give 5-58 g (70%) of the addition compound 7v as a white powder. To a solution of the aldol addition compound 7v (4.00 g, 10.0 ·· 01) in toluene (100 ml) was added p-toluenesulfonic acid hydrate (20 Bg). The mixture was heated to reflux for 30 minutes. The reaction mixture was washed twice with water (200 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was subjected to column chromatography on a silica gel, and the fractions eluted with n-hexane / ethyl acetate (3: 1) were collected, concentrated in vacuo, and recrystallized from a n-hexane / ether mixture to obtain 1.346. g (40%) of the mesh gadolinium compound was colorless crystals. Compound 8Id: mp = 152-1541C. IRiNujoDcm1: 3608,2914,1638,1597,1461.1376,1285, 1214, 1133. NMR (CDC13) 5: 1.45 (18H, s, 2x BuM, 2.31 (2H, q, J = 7Hz, CHa), 3.00-3.07 (4H, m, 2x CHS), 5.51 (1H, s, OH), 7.22 (1H, t, J = 2.6Hz, CH), 7.26 (2H, s, Ar-H) . Element analysis (CisHaeOaS> Calculated value: C, 67.82; H, 8_38; S, 9.53 This paper size applies to China National Standard (CNS) A4 specification (210X25) 7 Gongchu). 1 1-:----- 111 Order I-. 4. (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention U〇

Measured value: C, 67.90;;, 8.38; S, 9.34. Examination example 34 ^ 丨 Second-third Dingmou-4-Xiang 1 Benzyme-2-Shenmou-H

CHO V0 +

N-Me-LD-^-O 4jl

OH

p-TsOH Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

According to a similar method as in Example 1, N-methyl-1,3,2-thiazepine-co--1,2-dioxolidine (575, 3.80 «〇1) and 3,5-di-third-butyl 4-methoxymethoxybenzaldehyde 6a (846ag, 304 mm) was subjected to an aldol reaction to obtain 1.458 g of the addition compound 7w as a white powder. P-toluenesulfonic acid was added to a solution of aldol addition compound 7w (1.458g) in toluene (50 oz. 1). The paper size is applicable to Chinese National Standard (CNS) A4 (2 丨 0 X 297 mm) 62 I . „--- .; --- " L--installation ------ order ------ brigade (please read the precautions on the back before filling out this page) Staff of Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperative A7 B7 V. Description of the invention (61) Hydrate (150Bg). The mixture was heated to reflux for 30 minutes. The reaction product was subjected to column chromatography on silica gel using n-hexane / ethyl acetate. The mixture of (6: 1) was dissolved and the dissolved fraction was obtained, and the obtained compound (511 as, 43%) showed colorless crystals. Compound 8Ie: 84, = 215-216.510. IRiKBricm1: 3599,3438,2960,1637,1599,1437 , 1326, 1298,1153. NMR (CDC13) 5: 1.44 (18H, s, 2x BuM.B.OOOH.s.CHa), 3.26-3.32 (2H (ni, CHa), 4. 12-4. 17 ( 2H, n, CHa), 5.49 (lH, s, OH), 7.15 (2H, s, Ar-H), 7.55 (1H, width, CH) · Elemental analysis (ClsHa9NCUS) Calculated value: C, 62.10; H, 7_95; N, 3.81; S, 8.72 Found: C, 62_03; H, 7 · 91; N, 3_92; S, 8_51

SJ @ L1S (FJ-6- (-flute three T certain -4- unloading) Di ^ certain -2-shen argon 3.4.5. 6-tetra argon -1. 9- 瞌 ntt -1 .1-di argon物 （8ΙΠ

This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm)----------- ^ ---- " L--packing ------ order ---- -^ -------- (Please read the notes on the back before filling this page) A7 B7

V. Description of the invention (62

0H

p-TsOH

N-methoxy-3,4,5,6-tetrahydro-1, 2-sleeper-1, dioxane 4s (2.73 g, 16-5 mmol) and 3,5-di- The third butyl-4-methoxymethoxybenzoxe 6a (5.0 mg, 18 mmol) was subjected to acid-alcohol reaction to obtain 7.3 g of addition compound 7x. To a solution of the aldol addition compound 7x (2.1 g, 4.73 mmol) in toluene (100 ml) was added p-toluenesulfonic acid hydrate (20Bg) and the mixture was heated to reflux for 30 minutes. The reaction product was subjected to column chromatography on a silica gel, and the title compound (750 mg, 42%) was obtained as a brown powder from the fraction obtained by dissolving M n-hexane / ethyl acetate (4: 1). IR (CHC13) cm-1: 3618,2950,1630,1435,1340,1238,1161. NMR (CDC13) §: 1.45 (18H, s, 2x BuM, 1.80-1.95 (2H, in, CHa), 3.04 ( 2H, t, J = 6.0Hz, CHs), 3.77-3.83 (2H, ia > CHa) I 3.80 (3H, s, 0CH3), 5.46 (lH.s, OH), 7.20 (2H, s, Ar-H ), 7.46 (lH.s, CH). This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) I. „--- ^-IL--installation ------ order-- ---- S. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ch3s〇2nC [h + 12 A7 B7 V. Description of the Invention (63) Fen Example 36 II- Diazepam-4-hundronyl) benzylidene-2-ethyl-1.2-lipidone-one-1. 1-digas (8 Ικ) (1) d 5-di-diazine -4-Shenqi Methyl Argonyl Methionyl) -N-Ethyl-N-Dioxine Shenshen Methane Tyramine (14)

OMOM

LiHMDS YA / OMe

conC

Me 13 11— I n Ml i — J I I -— (Please read the notes on the back before filling this page)

.? τ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (bh = ch (c6h5) 2 M The conventionally synthesized compound (II) is obtained by the presence of methanesulfonyl chloride and diphenylmethylamine in triethylamine The reaction is followed by treatment of the product with ethyl iodide in the presence of potassium carbonate. The method for preparing compound (11) is to convert 3,5-di-third-butyl-4-hydroxybenzoic acid to hydrazone by conventional methods. Chlorine, and the fermentation gas with Ν, Ο-dimethylhydroxylamine, followed by a methoxymethylation reaction of the phenolic strip hydroxyl. Compound (12J (16.82g, 58 ·· Ι) in THF < 200ml) Λ This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) A7 B7 V. Description of the invention (64) Liquid cooling to less than -50 ° C. Lithium trimethylsilylamine is slowly added dropwise into the solution. The solution and mixture in THF (1.0M) (64 · 1, 64 ·· ο1) were stirred at -50t for 30 minutes. Then the solution of the compound (LI> (17.7g, 52.2 Mol) in THF (100inl) was slowly washed one by one. The mixture was added dropwise. After the reaction solution was warmed to room temperature, a saturated aqueous solution of ammonium chloride (500 ml) was added thereto. The resulting mixture was acetic acid Ester (400ml) was extracted. The organic layer was taken out, washed with a saturated sodium hydrogen persulfate aqueous solution (500ml) and saturated brine (500ml), dried over anhydrous sodium sulfate and evaporated in vacuo to remove the solvent. The residue was borrowed on a silica gel column Purified by chromatography and dissolved in n-hexane / ethyl acetate (9: 1 to 7: 1) to give 27_2g (92%) of compound U as a colorless oil. IR (CHC13) cni-1: 2960,1673,1339, 1188. NMR (CDCU) 5: 0.83 (BH, t, J = 7.0Hz, CHa), 1.45 (18H, s, 2X fBu), 3.56 (2H, q, J = 7.0Hz, CH *), 3.65 (3H , s, CH3), 4.37 (2H, s, CHS), 6.42 (1H, s, CH), 7.3 and 7.38 (10H, m, 10X aromatic-H), 7.89 (2H, s, 2X aromatic-fluorene) ). I ------- r--install ------ order ---------- t (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives (2) Di 孑 -Ding Shi-3- (3.5-Second-Di San Dingxi-4-Tian Du. Ar Rong Jia Bing, -3- (NZ-N-N-Erhu, Tian Very pussy sugar) Bing 酴 cool (1 5)

Five ', description of the invention (65 A7 B7 〇

S〇2N: C02'Bu

.Et 'BH

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (3,5-di-third-butyl-4-methoxymethoxybenzyl) -N-ethyl-N-diphenylmethylmethanesulfonamide (II> (27.0 g, 47.7 mmol), a third butyl bromoacetate (9.25 ml, 57.3 mmol), and a suspension of potassium sulphate (9.89 g, 71.6 mmol) in DMF (300 ml) was stirred at room temperature for 18 hours Water was added to the suspension and the reaction mixture was extracted with ethyl acetate (800 ml). The organic layer was separated, washed with water (300β1) and saturated brine (500 ml), dried over anhydrous sodium sulfate and distilled under vacuum to remove the solvent. The obtained pale yellow solid was thoroughly washed with n-hexane and concentrated in vacuo to obtain 26.75 g (82%) of compound 15 as a colorless powder (mp = 104-105t :). IR (KBr) cm-1: 3435, 1735, 1677,1340,1164,1147. NMR (CDC13) S: 0.77 (3H, t, J = 7.0Hz, CH3), 1.21 < 9H, s, tBu), 1.44 (18H, s, 2x Mu), 2.83 ( lH, dd, J = 3.2, 16.8Hz, CHa X 1/2 >, 3-29-3.51 (3H, m, CHa + CHa x 1/2), 3.65 (3H, s, CH3), 4.90 (2H, s, CH2) > 5.28 (lH, dd, J = 3.2,10.4Hz) CH), 6.B9 (lH &s; s, CH), 7.3l -7.34 (1011, | 1,10 \ aromatic-1〇, 7.96 (211,3,2 > < Aromatic-1〇. Elemental elemental prayer (C3sHa3N0TS) Calculated value: C, 68.90; H, 7.86; N, 2.06; S, 4.72 Found: C, 68.80, · H, 7.93; N, 2_16; S, 4 · 55 · (3) Butyl-4- dR-a-di = Dingling Methane Arsenic cage): Phenylmethylamine still fermented) Butyric acid (1 R) This paper is applicable to China Family Standard (CNS) M Specification (2) 〇χ 297 公 楚 —— & -67 ___1 (Please read the precautions on the back before filling out this page)-Binding and ordering A7 B7 V. Description of the invention (66

S〇2N: C〇21Bu

.Et • BH

NaBH4 CHgC 丨 2_ ΜθΟΗ

OH

C02 * Bu

S〇2N

BH I, i In n · '--· ^^ 1-(Please read the notes on the back before filling out this page) In the third-butyl-3- (3,5-di-third-butyl- 4-methoxymethoxybenzyl) -3- (H-ethyl-N-diphenylmethylmethanesulfonyl) propionate (15) (22.6 g, 33.2 inmol) in MeOH (180nl) The solution of the mixture with CH »Cla (180 ml) was added in several portions under cooling with ice, and sodium borohydride (1.89 g, 49.9 aniol) was added. The resulting mixture was warmed to room temperature and stirred for 45 minutes. Then, acetone (5 ml) and a saturated ammonium chloride aqueous solution (400 ml) were sequentially added to the mixture, and the reaction mixture was extracted with dichloromethane (400 ml). The organic layer was separated, washed with M water (400 ml) and saturated brine (400 ml), dried over anhydrous sodium sulfate and vacuum distilled to remove the solvent. The resulting pale pink solid, when thoroughly washed with n-hexane, gave 21.8 g (96%) of the compound as a colorless powder. IRiKBrJcm-1: 3499, 2970, 1737, 1600, 1319, 1151. NMR (CDC13) 5: 0.84 (3H, t > J = 7.0Hz > CH3) > 1.21 (9H (sItBu), 1.41 (18H, s, 2xtBu), 2.22 (lH, dd > J = 6.6, 17.6Hz, CHexl / 2), 2.48 (lH, dd, J = 4.2,17.6Hz, CH, x 1/2), 3.37-3.58 (2H, m, CHa), This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

.1T Λ-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

A7 B7 V. Description of the invention (67 3, 62 (3H > S, CH3), 3.92-4.07 (1H, m, CH), 4.14 (1H, d, J = 2.2Hz; OH), 4.86 (2H, s, CHa), 4.97 (lH, dd, J = 2.2, 9.2 Hz, CH), 6.47 (1H, S, CH), 7. 19 (2H, s, 2X aromatic-H), 7.32-7.34 (10H, m, l〇x aromatic-H). Elemental analysis (C33HaeN〇7S · 0.7H »0 > Calculated value: C, 67.44; H, 8.18; N, 2.02; S, 4.62 Real tear value: C, 67.50; H, 8_06 ; N, 2.15; S, 4.51. ⑷ 第 ^-~ r 凌 -4- m- 二-三 丁丁 -4- 田 氩 申 窗. 芏 芏) -4-Hydroxy. Some storage sound pickled even) Ding 酴 ku Μ 7)

C02'Bu

OH ^ Et S02N

BH

[H2] Pd (〇H) / C THF-MeOH

OH

S02NHEt C02'Bu — „--- ^-ί--install -------- order ------ Λ. (Please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Tertiary-butyl-4- (3,5-di-tertiarybutyl-4-methoxymethoxyphenyl) printed by employee consumer cooperatives 4-hydroxy-3- (N-ethyl-N-di Phenylmethyl) -4-hydroxy-3- (N-ethyl-N-diphenylmethylaminesulfonyl) butyrate (L6J (20.8g, 30.5mmol) and hydroxide / sulfonate (3.05 g) Suspension in a mixture of THF (100nl) and methanol (200 channels 1) at room temperature under hydrogen for 5 hours. Applicable to Chinese National Standard (CNS) A4 size (210x297 mm) A7 paper size B7 V. Description of the invention (68) Plastic filter (celite) to remove the solvent and concentrate the filtrate. The residue was recrystallized from ether-n-hexane to obtain 13.69 g (87%) of the compound 〇! _) (Β · ρ · = 96 -9710). IR (KBr) cm-1: 3441,3298,2966,1736,1635,1367,1152. NMR (CDC13) §: 1.15 (3H, t, J = 7.4Hz, CH3), 1.36 < 9H , s, * Bu), 1.44 (18H, s, 2x ^ Bu), 2.31 (lH, dd, J = 5.6,17.6Hz, CHax 1/2), 2.80 (1H, dd, J = 6.6,17.6Hz, CH * x 1/2), 3.00-3.27 (2H, m, CH *), 3.40 (lH, d, J = 4.8Hz, 0H), 3.64 (3H, s, C H3), 3.97 (lH, ddd, J = 5-6, 6.6, 8.2 Hz, CH), 4.19-4.25 (lH, m, NH>, 4.89 (2H, s, CHa), 4.95 (111, (1 (1, < 1 = 4.8,8_2112, (: 1〇, 7_27 (211,3,2 \ aromatic-1〇 · elemental analysis (CaeH4eN07S) calculated value: C, 60.56; H, 8.80; N, 2.72; S, 6.22 found Values: C, 60.37; H, 8.72; N, 2.69; S, 6.17. (5) 5-Di-DiSanDingMou-4-WuRongYi) -4-f. Meat Ester (18) I «I Jmmf HL In * ^-々 (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

OH

S02NHEt C02lBu

TMSI CHCI,

S02NHEt 18

-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7 --------------- V. Invention Description (69) for tert-butyl-4- (3,5-di-tert-butyl-4-methoxymethoxyphenyl) -4-hydroxy-3- (N-ethylaminesulfonyl ) Butyrate 〇! _) (1.10g, 2_13 mmol) in a gas-form (30ml) solution was added with iodine trimethylsilane (TMSI> (0_91ml, 6.39Bmol)) and the resulting solution under ice cooling in one portion After stirring at the same temperature for 30 minutes, after adding a 5% sodium sulfonate aqueous solution (70 ml), the reaction mixture M digas methane (60 · 1) was extracted twice. The combined organic layers were washed twice with saturated brine (70 ml) K was dried over anhydrous acetic acid and the solvent was removed by vacuum distillation. The residue was purified by column chromatography on silica gel, and the solvent was dissolved in n-hexane / ethyl acetate (3: 1) to obtain 481 mg (57%) of compound (11). Colorless solid. Mp = 129-131C. IR (CHCl3) cm-1: 3626,3374,3288,2960,1785,1436,1331. NMR (CDC13) 5: 1.08 (3H, t, J = 7.2Hz, CH3) , 1.44 (18H, s, 2 x " Bu) (2.90-3.22 (2H, m, CH2), 3.07 (2H, d, J-7.6Hz, CHs), 3.94 (lH dt, J = 5.0, 7.6 Hz, CH>, 4.25 (1H, wide, t, J = 6.0 Hz, NH), 5.38 (1H) S) 0H), 5.72 (lH, d, J = 5.0 Hz, CH) , 7.12 (2H, s, 2X aromatic-H). Elemental analysis (CmH ^ NC ^ S) Calculated value: C, 60.43; H, 7_86; N, 3.52; S, 8.07 Found: C, 60.32; H, 7.84; N, 3.55; S, 7.85. ⑹ 红 丄 二 1 _- (3.5-di-third butyl-4-Ci Rongmou, -2-〇1-7. Even)-Ding Luo 酴 f1Q) paper Standard size "Medium A4 size (210X297 mm) ---------- Installation ------ Order ------., 1 (Please read the precautions on the back before filling this page ) A7 B7 V. Description of the invention (70)

DBU benzene

19 Printed by 5- (3,5-di-tertiarybutyl-4-hydroxyphenyl) -4- (N-ethylaminesulfonyl) -r-butane Ester (ISJ (l_516g, 3_81β · ο1) was added to a solution of benzene (50 ml) in DBU (1.14 ml was 7.62 mmol) and the mixture was stirred under the same conditions for 30 minutes, and then 1NHC1 (60b1) was added. Reaction mixture M ethyl acetate Ester (70 nl) was extracted. The organic layer was separated, washed with M water (60 Bl) and saturated brine (60nl), and dried with anhydrous sodium sulphate. The solution was distilled under vacuum to remove the solvent to obtain 1.52 g (quantitative) of Compound 1 9 It was colorless and solid. M. P. = 169-172t: IR (KBr) cm-1: 3604, 3267, 2958, 1719, 1631, 1596, 1430, 1326, 1158. NMR (CD3〇D) 5: 1 15 (3H, t, J-7.4Hz, CH3), 1.43 (18H, s, 2 x " Bu), 2.99 (2H, q, J = 7.4Hz, CHS), 3.63 (2H.S.CH, ), 7.29 (2H, s, 2x aromatic-H), 7.58 (lH, s, CH). Elemental analysis (CaeH31N0eS> Calculated value: C, 60.43; H, 7.86; N, 3.52; S, 8.07 Found: C, 60.36; H, 7.95; N, 3.54; S, 7.87. ⑺IE) -5- (into di-ditributane-4-hydroxy) Mouwu · Mou-1. 2-Isopyridine_pyridine-1 .1-Diargon Substance (8Ig) China National Standard (CNS) A4 Specification (210X297 mm) -WWi I. ^ ---------- Installation ------ Order ------, ^ * · (Please read first Note on the back, please fill out this page again) 5. Description of the invention (Ή) A7 B7

CIC〇2Et NEt3 〇

(Please read the precautions on the back before filling out this page). Packing. 81 g printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs at (£) -4- (3,5-di-tert-butyl-4-hydroxy Phenyl) -3-(^ ethylaminosulfonyl) -3-butenoic acid Il_ (1.52g, 3-81mmol) and triethylamine (0.737ml, 1.5 equivalents) in dichloromethane (60ml) In the solution, ethyl gas sulfonate (0.437 ml, 1.2 equivalents) was added dropwise with cooling with water and stirring with M, and the mixture was stirred for another 50 minutes. After adding water (60 ml), the reaction mixture was extracted with dichloromethane (50 ml). The organic layer was washed with saturated brine (70 ml), dried over anhydrous sodium sulfate and distilled under vacuum to remove the solvent. The obtained crude crystals were washed with ether to obtain 1.30 g (89.9%) of the mesh gadolinium compound as colorless crystals. Compound 8Ig: Bp = 188-19010. IRCKBrJcm-1: 3559, 2960, 1715, 1641, 1598, 1434, 1317, 1159. NMR (CDC13) 5: 1.38 (3H, t, CH3), 1.46 (18H, s, 2x BuM, 3.74 (2H, q, J = 7.2Hz, CHa), 3.80 (2H, d, J = 2.4Hz, CH ``), 5.64 (1H, s, 0H), 7.23 (2H, s, Ar-H), 7.45 (1H, t, J = 2.4Hz, CH).

、 1T -Λ This paper size applies to China National Standard (CNS) A4 specification (2! OX 297 mm) A7 B7 ◦ \ v > 〇

V. Description of the invention (72) Elemental analysis (CsoHusNCUS) Calculated value: C, 63.30; H, 7.70; N, 3.69; S, 8.45 Found: C, 63.07; H, 7.71; N, 3.72; S, 8.30 Example 37 (£) -5- (3.5-Di-Di Er. Ding Mou-4-Hou) Fei ¥ 2-2-7.Mou 3-Zhen 1.2-Liblazidine-1.1-Digas f8Thl

DIBAL

In a solution of compound 8Ig (870mg, 2.29mmol) in dichloromethane (30ml) was stirred with K 搂 and cooled to below -40Ό. Diisobutylaluminum hydride (DIBAL) in hexane (1-0M, 4 · 22η1). After about 5 minutes, a saturated aqueous ammonium chloride solution (30 ml) was added to the reaction mixture, and the resulting slurry was filtered through acetam plastic. The filtrate was added with a saturated aqueous ammonium chloride solution (70 ml) and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and evaporated under vacuum to remove the solvent. The obtained crude crystals are re-settled from a mixture of n-hexane / ¾. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1 ^ ------ Λ--packing ------ order- -----, Α (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

A7 B7 i. Description of the invention (73) Crystals were obtained to obtain 762 mg (87.2%) of the mesh hydrazone compound as colorless crystals. Compound 811: 111.?. = 138-141 < 0 · ^ (KBrJcm-1: 3610,3427,2968,1653,1595,1432,1261, 1214,1147. NMR (d6-acetone > δ: 1.27 (3H , T, J = 7.0 Hz, CH3>, 1.48 (18H, s, 2x Bu *), 3.01-3.12 (IH.b.CH), 3.27 (2H, q, J = 7.0Hz, CH »), 3.57 ( lH, n, CH), 5.21-5.24 (1H, b, CH (OH) >, 5.35 (1H, wide, OH), 7.18 (1H, t, J = 2.4Hz, CH), 7.37 (2H , s, Ar-H). Elemental analysis (CaDH3lN0 * S > Calculated value: C, 62.94; H, 8.19; N, 3.67; S, 8.40 Found: C, 63.05; H, 8.26; N, 3.67; S, 8.33. Fen Example 38 (R) -5- (3 · 5-Di- 筮 三 丁某-/ t- 挥) 盱 ¥ -2--2-. Very-di-M-5Η-1. 2-Li 暄 11 $ DING-1. 1-Diargonide (8ΤΠ, 々〇N-Et H + 'Η —J --- Ί11 ---- install ------- order -------- 京 i (please (Read the notes on the back before filling out this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Et Zhang-Paper Standard Applicable to a country I China Appropriate centimeter 7 9 2

A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs i. Description of Invention (74) To a solution of compound 8Ih (342mg, 0.896mmol) in THF (30ml) was added 2N-hydrochloric acid (1 drop). The mixture was stirred at room temperature for 3 hours and a saturated aqueous sodium hydrogenpersulfate solution (35ral) was added. The reaction mixture was extracted with ethyl acetate (30 ml), and the organic layer was washed with saturated brine (35 ml), dried over anhydrous sodium sulfate and evaporated under vacuum to remove the solvent. The obtained crude crystals were recrystallized from a mixture of n-hexane / ether to obtain 296 mg (90.8%) of the mesh compound as orange crystals. Compound 81 i: bp = 135-137¾. IRiKBrJcm1: 3608,3472,2961,1593,1560,1435,1392, 1300,1212,1153. NMR (CDCla) 5: 1.40 (3H, t, J = 7.2Hz, CH3 ), 1.43 (18H, s, 2 x BuM, 3.52 (2H, q, J = 7.2Hz, CHa), 5.50 (1H, s, OH), 6.22 (IH.dd, J = 0.8,6.2Hz, CH), 6.54 (lH, dd, J = 1.8, 6.2Hz, CH), 6.84 (1H, width, CH), 7_30 (2H, s, Ar-H). Elemental analysis (Cs DHa sN03S > count value: C, 66.08; H, 8.04; N, 3.85; S, 8.82 Found: C, 6653; H, 8.08; N, 382; S, 8_68 Csf 1) R3NH2 〇〇2) POCI3 5 (r3 = ch, ch2ch3) Isopropylpyridine-1, argon servant Up)

(Please read the notes on the back before filling this page).

、 1T Spring Standard I / JC Printed by A7 _ B7 of Employees' Cooperatives of Central Standards Bureau of the Ministry of Economic Affairs of Balin Li Kong. 5. Description of Invention (75) In Cyclopropane (r-sulton) (12_2g, 0.1mol) The n-propylamine (5.9 g, 0.1 mm) was added with stirring and cooling with internal M. As the reaction proceeds, the contents solidify. Phosphorus chloride (10) is added to the solid product. The reaction mixture was heated to reflux for 2 hours and then evaporated under vacuum to remove the remaining phosphine gas. After ether (100 ml) was added to the residue, insoluble matter was removed by filtration. The ether layer M was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the compound 4e (15.2 g, 93%) as a colorless oil. This osmium product is consistent with a real sample obtained in Preparation Example 5. Participant Li 2 (R3 = CH2CH (CH3) ») N-Ridin-1.2-Ridin0 $ pyridine-1.1-Diargon. (4c) According to a similar method as in Reference Example 1, propanone (12.2 g, 0.1 mol), isobutylamine (7.3 g, 0.1 mol) and phosphonium chloride (10b1) were reacted to obtain the compound 4c (15.9 g, 93%). This product is consistent with the real sample obtained in Preparation Example 3. The compound of formula I of the present invention prepared as the above example was evaluated for its efficacy as an anti-inflammatory substance in test tubes and in vivo tests. One of the reference compounds E-5110 used in the following experimental examples is N-methoxy-3- (3,5-di-third-butyl-4-hydroxybenzylidene) described in Japanese Patent Laid-Open No. 257967/1986 -2-pyloridine.窨 Experiment 1 on rat synovial cell pairs? Inhibitory activity produced by ^ 8 Synovial group of male LEW / Crj rats (weighing 300-350g) were collected and subcultured under stable conditions until the number of cells was sufficient for the test. M4-103 cells / 160wl / Well placed in a 96-well plate and at Coa This paper size applies to China National Standard (CNS) A4 (210X297 mm)

— ^ --- \ ------ install ------ order ------ ^ F (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs System A7 B7 V. Description of the invention (76) Incubator for 72 hours. A solution (20m1) was added to each well at the same time. The solution contained undetermined drugs and human IL-1 / 3 (20W1) (final concentration: 30U / ml), and the reaction was performed in a COa incubator for 15 hours. The supernatant was stored at -80C until PGE was measured. After thawing the preserved samples, iaeI-PGE was used to measure PGEa by RIA. The results are shown in the table below. 〇 Example 2 Inhibition of LTB4 production in rat abdominal cells

Jci-SD male rats (weighing 300-350g) were intraperitoneally injected with Hank's solution (10ml), which contained 0.1% bovine serum albumin (BSA) and 25U / ml heparin. The ascites were collected and centrifuged for 5 minutes at 4 μM 150 Γρπ. The cell fraction (precipitate) was suspended in Hank's solution containing 0.1% BSA and the cell density was adjusted to 1 × 10B cells / ml. The adjusted suspension (800 <8; 8X 10β cells) was transferred into a polypropylene tube and incubated at 371C for 10 minutes. After adding a solution (100 »1) containing the drug to be tested at various concentrations, the tube was incubated for another 10 minutes, and then Ca-ion group A23187 (100 μl; final concentration, 1 μM) was added. The reaction was carried out for 15 minutes and then stopped by adding ice cooling. The suspension was centrifuged at 3000 rp for 5 minutes at 4¾ to collect the supernatant. The supernatant was stored at -801C before measurement. After thawing the preserved samples, 3H-LTB4 was used for RTB * measurement by RIA. The results are shown in Table 1 below. Trial example 3 THP-1 cells were inhibited for IL-1 production under LPS stimulation. THP-1 cells were evenly dispersed in RPMI 1640. 800W1 homogeneous solution (5X106 cells / Hole), 100ttl solution and paper containing non-standard paper applicable to China National Standard (CNS) A4 specification (2 丨 0 X 297 mm)

---- Ί ---_--.-- pulling clothes --- I n- ------ bundle L ---. (Please read the precautions on the back before filling this page) A7 B7 Five 2. Description of the invention (77) Drugs to be tested at equal concentrations and 100wl LPS (final concentration 100iig / ml) were opened for reaction. The reaction mixture was allowed to stand at 371C for 24 hours. The supernatant was collected and centrifuged at 3000 rpm for 10 minutes. The IL-1 measurement of the supernatant was performed using &quot; oi-IL-l / S by RIA. The results are shown in Table 1 below. UL · test tube test results, please read the note above

Compound number R3 PGE2 (rat ic50 (μΜ) LTB4 (rat PPΓΜ IL-1 (ΤΗΡ-1)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 8a Et &lt; 0.001 6.0 10 8b Me &lt; 0.001 2.8 21 8f OMe 0.001 3.0 &gt; 100 0 0 Bu V 8g och2h6h5 0.18 2.5 11 XjT0i ^ z 81 1.0 3.0 19 HO t-Bu 8w CONHOH 0.024 6.0 20 100 8u CON (OMe) M e 0.1 28 10a H 0.03 &gt; 100 &gt; ιο〇11a OH 0.013 9.5 90 8b Me &lt; 0.001 1.8 29 Eight factories i, ') 8f OiMe &lt; 0.001 1 · 5 — ηοΎ 〇i ~ f! T-Bu 0 H3 81 2-pyridyl &gt; 1 1.4 100 90 11b OH 0.012 9.6 E-5110 C.005 6.0 &gt; 100 indomethacin Xin 0.002 &gt; 100 &gt; 100 __- Endemic example 4 · The experimental study on the inhibitory activity of carrageenan-induced edema in rats is based on the Winter's method (Winter, CA et al_, Proe · This paper is applicable to China Standard (CNS) Eight-four specifications (210 X 297 mm) Decision iS [· Order the Central Consumer Bureau of the Ministry of Economy Staff Consumer Cooperatives Co., Ltd. Yin Li Α7 Β7 V. Description of the invention (78)

Soc. Exp. Biol. Med ·, vol.lll: 54 (1962) with minor modifications. Yidi LEW / Crj male rats (6 weeks old, weighing 140-170g) were fasted for 24 hours, divided into arrays, each group containing 7 To 8 rats. 1 hour after the administration of the drug, 0.1 ml of a 1% λ-carrageenan (PICININ-A, Zushikagaku) solution was injected subcutaneously into each animal, and the injection site was edema caused by the plantar of the right hind leg. And 5 hours every 1 hour after injection, the volume of the right hind leg was measured by a water displacement method using a volumetric meter. According to the Dunnett-t test, the drug was evaluated by calculating the edema suppression rate of the administration group relative to the vehicle administration group. Efficacy. The anti-edema effect of the drug, MEDbd (mg / kg), is based on regression analysis of inhibition rate. This ED can be obtained 3 or 4 hours after carrageenan administration. The results are shown in Table 2 below. LEW / Crj male rats (6 weeks old, weighing 140-160g) were divided into groups of 6 rats per group according to the amount of test drug. Animals were administered on an empty stomach 24 hours before the test and in The animals were anesthetized with ether 6 hours after administration and killed by exsanguination. Normal saline (approximately 6ml). Then the stomach is immersed in 15% formalin solution for about 15 minutes and cut along the large curve. Observe the gastric lesions using a stereoscopic microscope. Calculate the number of rats showing gastric lesions and bleeding plaque Length. The degree of lesion is expressed by the lesion index (mm), and the lesion index is a progressive value of the length of bleeding plaque in each administered tissue. The intensity of drug efficacy MUDee (mg / kg) is expressed. UDu uses the Probit method based on the administration of a specific dose of the drug group. The number of cases showing lesions was calculated. The results are shown in Table 2 below. This paper size applies to China National Standard (CNS) A4 (210 × 297 mm) ml- ►11 m · · nn ^ l —J HI US (Please read the notes on the back before filling out this page) Order Λ V. Invention Description 79 You 涸 {Γτπϊ &gt;; Ε — 5110 A7 B7 I {bn! &Gt;

O O V-〇 &gt;

Cs &gt; N &gt; JU · CTv o Η-»» — ** — * DO to LO — o 〇- &gt; &lt; J \ CJ \

-~ 4 ——J -'J i— »K- * t—1 K &gt; CO Cs &gt;

CTN O Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs &gt; 400 \ X &gt; 〇〇— iooooo ΟΊ »— OO CTs ^ O'JHUn VJ1 V &gt; J-« 4 OO OO 1+ 1+ 丨 + 丨 + 1+ 1+ 1+ 1+ 1+ 1 + C〇i ~ »&lt; Z &gt; 0 t〇 &gt; — *» — *! — * 〇0 &gt; — * ΟΊ vO-&lt; J 〇J OJ U1 仏 — J — to 00 ± ° 00 04 Ι + 004 00 Ι + Ρ 00 17 Ι + 0. 17 5 Ι + Ρ 03 ^ Φ ^ ^ 0 = 娉 涊 _ Ｍ 娉 涊 娉 涊 娉 涊 遡 筘 洚 key 31 洚 a aR 苕 遡 筘 SLINGΠ Ms / kg UD = 3131, total enthalpy day g / k '/ «(5) 8a left 0 &gt; wrong E-5110 ss 卅

〇 UJ OO (Please read the notes on the back before filling this page)

Et (ΕΓ)% This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm): 81-^ 7o2G7 at B7 V. Description of the invention (80) It is clear from the experimental results that the compounds of the present invention can be inhibited The activities produced by PGEa, IL-1, etc. have no serious side effects on the gastric mucosa, and are expected to be used as active ingredients in pharmaceutical formulations for the treatment of inflammatory diseases. Chiaberry adjusts g_ granules Compound 8a 20mg Lactose 250ag Corn starch 115mg Hydroxypropylstrylavirin 115ng Μ Each material on the conventional wet granulation method is used to obtain granules. m. f I n. I--—1-1 ^^ —I— n ^ i HI ·-I-^^ 1 In: —— ϊ · ^ t Please read the notes on the back and fill in this Va 〇 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

^ Years _ 丨 8 &amp;. \ 六 、 Scope of patent application Λ8 B8 C8 D8 No. 82108811 reexamination application Patent scope amendments Date of amendment: 1988 September 1. A compound such as formula I In the printed form of the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, A is -CH2- or -CH2CH2-; B is. One-click or -CH2-_, -CHOH- '-CO-, -Ο-, or a and B Can be combined to form -CH = CH &lt; D is &gt; 1 or &gt;B; R1 and R2 are each independently hydrogen, Ci-C5 alkyl or Ci-Ca alkoxy; R3 is hydrogen, and ^ -Cs alkane C · »-〇C5 ring alkyl group 'CfC3 alkyloxy group' 〇6_aryl alkyloxy group, nitrogen-containing heterocyclic aromatic alkyloxy group, CrCs alkylcarbonyl group, aromatic group, carbonyl group, amine Formamyl, amidomethyl substituted by CVC3 alkyl, CfCs alkoxy, c6-arylalkoxy, CrC3 alkyl Ci-C3 alkoxy, or hydroxyl group or a group of the formula:-(CH2 ) n-R4 where R4 is an amine group substituted by amine group or alkynyl group, and ^ group is aryl group which is mono- or di-substituted by CfC3 alkoxy group or halogen, and contains nitrogen atom as hetero atom. Heteroaryl, hydroxycarbonyl or fluorenyloxycarbonyl; n is an integer from 0 to 3. 2. If the compound of the scope of application for item 1, wherein R2 is a third butyl, respectively. 3. A compound as claimed in item 1 or 2, in which A is -CH2-; B is -CH2-, and 0 is &gt; N- ". \ I (fn-Ύ HI I ·! · 1 I n I ....... HI I —-1 ^ 1 (please read the notes on the back before filling this page) ^ Year_ 丨 8 &amp;. \ 六 、 Scope of patent application Λ8 B8 C8 D8 No. 82108811 No. Examination of the application for amendments to the scope of the patent amendment date: September 1988 1. A compound such as formula I In the printed form of the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, A is -CH2- or -CH2CH2-; B is. One-click or -CH2-_, -CHOH- '-CO-, -Ο-, or a and B Can be combined to form -CH = CH &lt; D is &gt; 1 or &gt;B; R1 and R2 are each independently hydrogen, Ci-C5 alkyl or Ci-Ca alkoxy; R3 is hydrogen, and ^ -Cs alkane C · »-〇C5 ring alkyl group 'CfC3 alkyloxy group' 〇6_aryl alkyloxy group, nitrogen-containing heterocyclic aromatic alkyloxy group, CrCs alkylcarbonyl group, aromatic group, carbonyl group, amine Formamyl, amidomethyl substituted by CVC3 alkyl, CfCs alkoxy, c6-arylalkoxy, CrC3 alkyl Ci-C3 alkoxy, or hydroxyl group or a group of the formula:-(CH2 ) n-R4 where R4 is an amine group substituted by amine group or alkynyl group, and ^ group is aryl group which is mono- or di-substituted by CfC3 alkoxy group or halogen, and contains nitrogen atom as hetero atom. Heteroaryl, hydroxycarbonyl or fluorenyloxycarbonyl; n is an integer from 0 to 3. 2. If the compound of the scope of application for item 1, wherein R2 is a third butyl, respectively. 3. A compound as claimed in item 1 or 2, in which A is -CH2-; B is -CH2-, and 0 is &gt; N- ". \ I (fn-Ύ HI I ·! · 1 I n I ....... HI I —-1 ^ 1 (please read the precautions on the reverse side before filling out this page) Α8 Β8 C8 D8 — ， the scope of patent application 4. The compound of scope 3 of the patent application, Its ㈣ is a morpho group or a cycloalkyl group. 5. A pharmaceutical composition for treating osteoarthritis, which contains the compound of the first range of interest as an active ingredient. 6. A medicament for treating rheumatism The composition contains the compound as the active ingredient in the patent scope item 1. 眚 (Please read the note on the back before filling out this page) • Order printed by the Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs-2- Standard for private paper: Common Chinese National Standard (CNS) A4 specification (2 丨 0 × 297 mm)